cgp-56697 and Malaria--Falciparum

Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy.. For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371.. We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92).. We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted.. Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Topics: Abortion, Spontaneous; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Ethanolamines; Female; Humans; Malaria; Malaria, Falciparum; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Prospective Studies; Quinine; Stillbirth

Half of all pregnancies at risk of malaria worldwide occur in the Asia-Pacific region, where Plasmodium falciparum and Plasmodium vivax co-exist. Despite substantial reductions in transmission, malaria remains an important cause of adverse health outcomes for mothers and offspring, including pre-eclampsia. Malaria transmission is heterogeneous, and infections are commonly subpatent and asymptomatic. High-grade antimalarial resistance poses a formidable challenge to malaria control in pregnancy in the region. Intermittent preventive treatment in pregnancy reduces infection risk in meso-endemic New Guinea, whereas screen-and-treat strategies will require more sensitive point-of-care tests to control malaria in pregnancy. In the first trimester, artemether-lumefantrine is approved, and safety data are accumulating for other artemisinin-based combinations. Safety of novel antimalarials to treat artemisinin-resistant P falciparum during pregnancy, and of 8-aminoquinolines during lactation, needs to be established. A more systematic approach to the prevention of malaria in pregnancy in the Asia-Pacific is required.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Asia; Female; Humans; Lactation; Malaria; Malaria, Falciparum; Pregnancy

Plasmodium falciparum infections are a relatively rare but potentially deadly disease found in returning travellers. We compare the national treatment guidelines of non-endemic countries with the WHO guidelines for the treatment of Plasmodium falciparum infections.. Review. We identified non-endemic countries with an incidence rate of imported malaria of at least one per 100,000 population and at least 50 cases annually. Using PubMed and Google Search, we reviewed national guidelines published before 1 March 2021.. Thirteen guidelines were identified. For uncomplicated falciparum malaria, 11 of 13 countries (85%) recommend an artemisinin-based combination therapy as first-line regimen in adults, of which artemether-lumefantrine was the most common. For severe malaria, all guidelines recommend the use of intravenous artesunate. Only three countries adjust treatment recommendations based on expected artemisinin resistance.. Treatment guidelines for uncomplicated falciparum malaria in non-endemic countries generally adhere to WHO recommendations but often fail to mention the risk of drug resistance in returning travellers. Artemisinin-based Combination Therapies (ACTs) should be the first choice for all uncomplicated malaria cases. Furthermore, the choice between ACTs should be based on regional resistance patterns.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Drug Resistance; Guidelines as Topic; Humans; Malaria, Falciparum; World Health Organization

The efficacies of artemisinin based combinations have been excellent in Africa, but also comprehensive evidence regarding their safety would be important. The aim of this review was to synthesize available evidence on the safety of dihydroartemisinin-piperaquine (DHA-PQ) compared to artemether-lumefantrine (AL) for the treatment of uncomplicated Plasmodium falciparum malaria among children in Africa.. A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Center for Clinical Trial database (CENTRAL) for retrieving randomized control trials comparing safety of DHA-PQ and AL for treatment of uncomplicated P. falciparum malaria among children in Africa. The search was performed from August 2020 to 30 April 2021. Using Rev-Man software (V5.4.1), the extracted data from eligible studies were pooled as risk ratio (RR) with 95% confidence interval (CI).. In this review, 18 studies were included, which involved 10,498 participants were included. Compared to AL, DHA-PQ was associated with a slightly higher frequency of early vomiting (RR 2.26, 95% CI 1.46 to 3.50; participants = 7796; studies = 10; I. From this review, it can be concluded that early vomiting, diarrhoea, and cough were common were significantly more frequent in patients who were treated with the DHA-PQ than that of AL, and both drugs are well tolerated. More studies comparing AL with DHA-PQ are needed to determine the comparative safety of these drugs.

Topics: Adolescent; Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Randomized Controlled Trials as Topic

Sub-Saharan Africa has the highest burden of malaria in the world. Artemisinin-based combination therapies (ACTs) have been the cornerstone in the efforts to reduce the global burden of malaria. In the effort to facilitate early detection of resistance for artemisinin derivatives and partner drugs, WHO recommends monitoring of ACT's efficacy in the malaria endemic countries. The present systematic meta-analysis study summarises the evidence of therapeutic efficacy of the commonly used artemisinin-based combinations for the treatment of uncomplicated P. falciparum malaria in Sub-Saharan Africa after more than a decade since the introduction of the drugs.. Fifty two studies carried out from 2010 to 2020 on the efficacy of artemether-lumefantrine or dihydro-artemisinin piperaquine or artesunate amodiaquine in patients with uncomplicated P. falciparum malaria in Sub-Saharan Africa were searched for using the Google Scholar, Cochrane Central Register of controlled trials (CENTRAL), PubMed, Medline, LILACS, and EMBASE online data bases. Data was extracted by two independent reviewers. Random analysis effect was performed in STATA 13. Heterogeneity was established using I2 statistics.. Based on per protocol analysis, unadjusted cure rates in malaria infected patients treated with artemether-lumefantrine (ALU), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DHP) were 89%, 94% and 91% respectively. However, the cure rates after PCR correction were 98% for ALU, 99% for ASAQ and 99% for DHP.. The present meta-analysis reports the overall high malaria treatment success for artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine above the WHO threshold value in Sub-Saharan Africa.

Topics: Africa South of the Sahara; Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Drug Combinations; Ethanolamines; Humans; Malaria; Malaria, Falciparum; Piperazines; Plasmodium falciparum; Quinolines

Artemisinin is an antimalarial compound derived from the plant Artemisia annua L., also known as sweet wormwood. According to the World Health Organization, artemisinin-based combination therapy (ACT) is an essential treatment for malaria, specifically Plasmodium falciparum, which accounts for most malaria-related mortality. ACTs used to treat uncomplicated malaria include artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulphadoxine-pyrimethamine, and dihydroartemisinin-piperaquine. Although the mechanism of action and clinical capabilities of artemisinin in malaria treatment are widely known, more information on the potential for drug interactions needs to be further investigated. Some studies show pharmacokinetic and pharmacodynamic drug interactions with HIV antiviral treatment but few studies have been conducted on most other drug classes. Based on known genotypes of cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A are primarily involved in the metabolism of artemisinin and its derivatives. Reduced functions in these enzymes can lead to subtherapeutic concentrations of the active metabolite, dihydroartemisinin, that may cause treatment failure, which has been shown in some studies with cardiovascular, antibiotic, and antiparasitic drugs. Although the clinical importance remains unclear to date, clinicians should be aware of potential drug-drug interactions and monitor patients on ACT closely.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Humans; Malaria; Malaria, Falciparum

Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy.. An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected.. In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.. Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Humans; Malaria, Falciparum; Plasmodium falciparum; Primaquine

Artemisinin-based combination therapy (ACT) was deployed in 2005 as an alternative to chloroquine and is considered the most efficacious treatment currently available for uncomplicated falciparum malaria. While widespread artemisinin resistance has not been reported to date in Africa, recent studies have reported partial resistance in Rwanda. The purpose of this study is to provide a current systematic review and meta-analysis on ACT at Mali study sites, where falciparum malaria is highly endemic.. A systematic review of the literature maintained in the bibliographic databases accessible through the PubMed, ScienceDirect and Web of Science search engines was performed to identify research studies on ACT occurring at Mali study sites. Selected studies included trials occurring at Mali study sites with reported polymerase chain reaction (PCR)-corrected adequate clinical and parasite response rates (ACPRcs) at 28 days. Data were stratified by treatment arm (artemether-lumefantrine (AL), the first-line treatment for falciparum malaria in Mali and non-AL arms) and analysed using random-effects, meta-analysis approaches.. A total of 11 studies met the inclusion criteria, and a risk of bias assessment carried out by two independent reviewers determined low risk of bias among all assessed criteria. The ACPRc for the first-line AL at Mali sites was 99.0% (95% CI (98.3%, 99.8%)), while the ACPRc among non-AL treatment arms was 98.9% (95% CI (98.3%, 99.5%)). The difference in ACPRcs between non-AL treatment arms and AL treatment arms was not statistically significant (p = .752), suggesting that there are potential treatment alternatives beyond the first-line of AL in Mali.. ACT remains highly efficacious in treating uncomplicated falciparum malaria in Mali. Country-specific meta-analyses on ACT are needed on an ongoing basis for monitoring and evaluating drug efficacy patterns to guide local malaria treatment policies, particularly in the wake of observed artemisinin resistance in Southeast Asia and partial resistance in Rwanda.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Humans; Malaria, Falciparum; Mali; Plasmodium falciparum

Plasmodium falciparum gametocytaemia has been associated with anaemia. The aim of this review was to synthesize available evidence on the comparative effect of dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL) on gametocyte clearance and haemoglobin recovery in children with uncomplicated P. falciparum malaria in Africa.. A systematic literature search was undertaken to identify relevant articles from online databases. The search was performed from August 2020 to 30 April 2021. Extracted data from eligible studies were pooled as risk ratios with 95% confidence intervals (CI).. Gametocyte carriage was reduced in both treatment groups, with no significant difference found between the groups. However, on days 28 and 42, a significant increase in serum haemoglobin level from baseline was observed in the DHA-PQ group (standardized mean difference 0.15, 95% CI 0.05-0.26; participants=2715; studies=4; I. DHA-PQ had a greater impact on haemoglobin recovery than AL on days 28 and 42; this difference was significant.

Topics: Africa; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Fluorenes; Hemoglobins; Humans; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Randomized Controlled Trials as Topic

The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.. To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.. The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.. Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.. For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.. Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with. Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.

Topics: Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Atovaquone; Cameroon; Child; Colombia; Drug Combinations; Ethiopia; Humans; Malaria, Falciparum; Mefloquine; Proguanil; Randomized Controlled Trials as Topic; Thailand; Treatment Failure

The emergence of artemisinin resistance in Southeast Asia and Plasmodium falciparum kelch13 propeller gene mutations in sub-Saharan African pose the greatest threat to global efforts to control malaria. This is a critical concern in Uganda, where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated falciparum. The objective of this study was to compare the efficacy and safety of dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in Ugandan children.. A search of PubMed and the Cochrane Central Register of Controlled Trials for retrieving randomized controlled trials comparing the efficacy and safety of DHA-PQ and AL for treatment of uncomplicated falciparum malaria in Ugandan children was done. The search was performed up to 31 August 2020. The data extracted from eligible studies and pooled as risk ratio (RR) with a 95% confidence interval (CI), using Rev Man Software (5.4). The protocol was registered in PROSPERO, ID: CRD42020182354.. Compared to AL, DHA-PQ appeared to reduce treatment failure and gametocyte carriage in Ugandan children. This may trigger DHA-PQ to become the first-line treatment option. Both treatments were safe and well-tolerated.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Humans; Infant; Malaria, Falciparum; Quinolines; Randomized Controlled Trials as Topic; Uganda

Regular monitoring of anti-malarial drug efficacy is vital for establishing rational malaria treatment guidelines and ensuring adequate treatment outcomes. This study aimed to synthesize the available evidence on the efficacy of artemether-lumefantrine for the management of uncomplicated falciparum malaria in Ethiopia.. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Relevant published studies were searched from the databases (PubMed, Google Scholar and Clinical trial registry) on published artemether-lumefantrine therapeutic efficacy studies conducted in Ethiopia from 2004 to 2020. The retrieved studies were assessed for quality using the modified Newcastle Ottawa Scale for observational studies and modified Jadad scale for interventional studies. Risk of bias was also assessed by using ROBINS-I tool. OpenMeta-Analyst software was used for the statistical analysis. The review protocol is registered in PROSPERO, number CRD42020201859.. Fifteen studies (1523 participants) were included in the final analysis. The overall PCR-uncorrected pooled proportion of treatment success of artemether-lumefantrine therapy for uncomplicated falciparum malaria was 98.4% (95%CI 97.6-99.1). A random-effects model was used because of considerable heterogeneity [χ. The present meta-analysis suggests that artemether-lumefantrine therapy is efficacious and safe in treating uncomplicated falciparum malaria in Ethiopia. However, owing to the high risk of bias in the included studies, strong conclusions cannot be drawn. Further high-quality RCTs assessing anti-malarial efficacy and safety should be performed to demonstrates strong evidence of changes in parasite sensitivity to artemether-lumefantrine in Ethiopia.

Topics: Artemether, Lumefantrine Drug Combination; Ethiopia; Humans; Malaria, Falciparum

Emergence of Plasmodium falciparum resistance to artemisinin and its derivatives poses a threat to the global effort to control malaria. The emergence of anti-malarial resistance has become a great public health challenge and continues to be a leading threat to ongoing malaria control efforts. The aim of this review was to synthesize available evidence on the efficacy of dihydroartemisinin-piperaquine (DHA-PQ) compared to artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria among children in Africa.. A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Central Register of Controlled Trials' database (CENTRAL) for retrieving randomized control trials comparing efficacy of DHA-PQ and AL for treatment of uncomplicated falciparum malaria in African children. The search was performed from August 2020 to April 2021. Using Rev-Man software (V5.4.1), R-studio and Comprehensive Meta-analysis software version 3, the extracted data from eligible studies were pooled as risk ratio (RR) with 95% confidence interval (CI).. In this review, 25 studies which involved a total of 13,198 participants were included. PCR-unadjusted treatment failure in children aged between 6 months and 15 years was significantly lower in the DHA-PQ treatment arm on day 28 than that of AL (RR 0.14, 95% CI 0.08-0.26; participants = 1302; studies = 4; I. From this review, it can be concluded that DHA-PQ reduces new infection and recrudescence on days 28 and 42 more than AL. This may trigger DHA-PQ to become a first-line treatment option.

Topics: Adolescent; Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Humans; Infant; Malaria, Falciparum; Polymerase Chain Reaction; Quality Control; Quinolines; Randomized Controlled Trials as Topic; Regression Analysis; Sensitivity and Specificity; Time Factors

The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas.. We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment.. We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission.. Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum

There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial.. A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very l. In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Female; Humans; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Parasitemia; Plasmodium vivax; Young Adult

In endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.. To evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.. We included randomised controlled clinical trials (RCTs) of paediatric versus non-paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.. Two authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non-paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.. Three trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ), and one trial assessed artemether-lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub-Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia). In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)-adjusted treatment failure rates of < 10% on day 28 in the per-protocol (PP) population. For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR-adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low-certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR-adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study). We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low-certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study). In the dispersible ACT arms, drug-related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA-PQ study. In the control arms, drug-related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA-PQ study. Drug-related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate-certainty evidence). There was no detected difference in the rate of drug-related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study). Drug-related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low-certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered. No study assessed acceptability.. Trials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug-related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bias; Child; Child, Preschool; Confidence Intervals; Drug Combinations; Humans; Infant; Malaria, Falciparum; Quinolines; Randomized Controlled Trials as Topic; Suspensions; Tablets; Treatment Failure; Vomiting

In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as 'clinical' or 'parasitological' failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.. A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.. Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6-49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.. AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Asymptomatic Infections; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Recurrence; Treatment Failure

Malaria is a worldwide health issue, with 216 million cases reported in 2016. Due to the widespread resistance of Plasmodium falciparum to conventional drugs, the first line treatment recommended by World Health Organization for uncomplicated malaria is artemisinin-based combined therapy (ACT), which combines two drugs with different mechanisms of action. The association of artemether and lumefantrine is the most common ACT used in the clinical practice. However, there have been reports of clinical artemisinin and derivatives partial resistance, which is defined as delayed parasite clearance. In this context, the monitoring of drug concentration in biological matrices is essential to evaluate treatment response, the need of dose adjustment and the occurrence of dose dependent adverse effects. Furthermore, it is also important for pharmacokinetic studies and in the development of generic and similar drugs. Determination of antimalarial drugs in biological matrices requires a sample pre-treatment, which involves drug extraction from the matrix and analyte concentration. The most used techniques are protein precipitation (PP), liquid-liquid extraction (LLE) and solid phase extraction (SPE). Subsequently, a liquid chromatography step is usually applied to separate interferences that could be extracted along with the analyte. Finally, the analytes are detected employing techniques that must be selective and sensitive, since the analyte might be present in trace levels. The most used approach for detection is tandem mass spectrometry (MS-MS), but ultraviolet (UV) is also employed in several studies. In this article, a review of the scientific peer-review literature dealing with validated quantitative analysis of artemether and/or lumefantrine in biological matrices, from 2000 to 2018, is presented.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Chemistry Techniques, Analytical; Drug Combinations; Drug Monitoring; Humans; Malaria, Falciparum; Sensitivity and Specificity

Artemisinin-based combination therapies (ACTs) are the first-line antimalarial drugs used to treat uncomplicated Plasmodium falciparum alaria in many endemic countries worldwide. The present work reviewed the therapeutic efficacy of ACT in Cameroon more than 10 years after the initial change in national drug policy in 2004.. A PubMed literature search was performed to analyse clinical trials conducted in Cameroon from 2001 to May 2017. Clinical studies that evaluated ACT for the treatment of uncomplicated falciparum malaria in children or adults, and reported efficacy and/or safety, were included. In addition, a small network meta-analysis (NMA) with a frequentist approach was performed.. Six papers were selected from 48 articles screened and were full-text reviewed. The efficacy of both artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) ranged from moderate to high, with polymerase chain reaction-corrected cure rates ranging from 96.7 to 100% and 88.2 to 100%, respectively, in per-protocol analysis, and 86.2 to 96.7% and 74.0 to 90.6%, respectively, in intention-to-treat analysis. The malaria evidence network suggested that AL and ASAQ efficacies were comparable. The highest day 3 parasite positivity rate was 8.2% for ASAQ and 4% for AL. A novel ACT, artesunate-atovaquoneproguanil (ASATPG) was tested once and showed a cure rate of 100%. Based on an ITT approach, the NMA revealed that AL was more efficacious than ASAQ, but the difference was not statistical significant (706 participants, three randomised clinical trials (RCT); OR 1.25, 95%CI 0.78-2.00). Adverse events ranged from mild to moderate severity but were not directly attributed to drug intake.. ACTs are still effective and safe in Cameroon; however, there are insufficient data on their efficacy, safety and tolerability, therefore more RCTs should be conducted, including novel ACTs.

Topics: Amodiaquine; Artemether, Lumefantrine Drug Combination; Artemisinins; Cameroon; Drug Combinations; Humans; Malaria, Falciparum; Plasmodium falciparum

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child, Preschool; Dose-Response Relationship, Drug; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Models, Chemical; Pregnancy

Ethiopia is among countries with a high malaria burden. There are several studies that assessed the efficacy of anti-malarial agents in the country and this systematic review and meta-analysis was performed to obtain stronger evidence on treatment outcomes of malaria from the existing literature in Ethiopia.. A systematic literature search using the preferred reporting items for systematic review and meta-analysis (PRISMA) statement was conducted on studies from Pubmed, Google Scholar, and ScienceDirect databases to identify published and unpublished literature. Comprehensive meta-analysis software was used to perform all meta-analyses. The Cochrane Q and the I. On the basis of this review, anti-malarial treatment success was high (92.9%) and standard regimens showed good efficacy against Plasmodium falciparum (98.1%) and P. vivax (94.7%) infections in Ethiopia, but associated with high rates of adverse drug reactions (ADRs). However, these ADRs were not serious enough to discontinue anti-malarial treatment. The results of this study suggest that the current anti-malarial medications are effective and safe; however, greater priority should be placed on the discovery of new anti-malarial drugs to achieve successful outcomes as resistance seems inevitable since cases of anti-malarial drug resistance have been reported from other areas of the world.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Drug Combinations; Ethanolamines; Ethiopia; Fluorenes; Humans; Malaria, Falciparum; Malaria, Vivax; Primaquine; Pyrimethamine; Sulfadoxine; Treatment Failure

As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this study was to synthesize the available evidence on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia. This was done by performing a meta-analysis of recent studies conducted in the country on this topic.. Studies published between January 2010 and January 2017 that reported on the efficacy of artemether-lumefantrine in the treatment of P. falciparum malaria in Ethiopian patients were searched for using the PubMed and Google Scholar databases. Ten prospective single-arm cohort studies that followed patients for 28-42 days were included in this analysis. All of the included studies were deemed to be of high quality.. Ten studies involving 1179 patients that were eligible for meta-analysis were identified. At recruitment, the average parasite count per patient was 1 2981/μl of blood. On the third day of treatment, 96.7% and 98.5% of the study subjects become fever-free and parasite-free, respectively. Based on the per protocol analysis, the cure rate after use of artemether-lumefantrine was 98.2% (polymerase chain reaction corrected) and 97.01% (polymerase chain reaction uncorrected) after 28 days of follow-up. The reinfection rate within 28 days was 1.1% and the recrudescence rate was 1.9%.. This review found that the cure rate for uncomplicated P. falciparum malaria using artemether-lumefantrine in Ethiopia is still high enough to recommend the drug as a first-line agent. There should be careful periodic monitoring of the efficacy of this drug, as treatment failure may occur due to resistance, sub-therapeutic levels that may occur due to non-adherence, or inadequate absorption.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Ethiopia; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum

The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treating people with Plasmodium falciparum malaria. Five combinations are currently recommended, all administered over three days. Artemisinin-naphthoquine is a new combination developed in China, which is being marketed as a one-day treatment. Although shorter treatment courses may improve adherence, the WHO recommends at least three days of the short-acting artemisinin component to eliminate 90% P. falciparum parasites in the bloodstream, before leaving the longer-acting partner drug to clear the remaining parasites.. To evaluate the efficacy and safety of the artemisinin-naphthoquine combination for treating adults and children with uncomplicated P. falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; and LILACS up to January 2015. We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'arte* OR dihydroarte*' as search terms.. Randomized controlled trials comparing artemisinin-naphthoquine combinations with established WHO-recommended ACTs for the treatment of adults and children with uncomplicated malaria due to P. falciparum.. Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.. Four trials, enrolling 740 adults and children, met the inclusion criteria. Artemisinin-naphthoquine was administered as a single dose (two trials), as two doses given eight hours apart (one trial), and once daily for three days (one trial), and compared to three-day regimens of established ACTs. Three additional small pharmaceutical company trials have been carried out. We have requested the data but have not received a response from the company. Artemisinin-naphthoquine versus artemether-lumefantrineIn three small trials from Benin, Côte d'Ivoire, and Papua New Guinea, both combinations had a very low incidence of treatment failure at Day 28, and there were no differences demonstrated in PCR-unadjusted, or PCR-adjusted treatment failure (three trials, 487 participants, low quality evidence). Only the single study from Papua New Guinea followed participants up to Day 42, and the number of treatment failures remained very low with both combinations (one trial, 186 participants, very low quality evidence). Artemisinin-naphthoquine versus dihydroartemisinin-piperaquineIn a single small trial from Indonesia, treatment failure at Day 28 and Day 42 was very low in both groups with no differences demonstrated (one trial, 144 participants, very low quality evidence).. The results of these few trials of artemisinin-naphthoquine are promising, but further trials from multiple settings are required to reliably demonstrate the relative efficacy and safety compared to established ACTs. Future trials should be adequately powered to demonstrate non-inferiority, and regimens incorporating three days of the artemisinin component are probably preferable to the one-day regimens.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Naphthoquinones; Quinolines; Randomized Controlled Trials as Topic

Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings.. We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites.. We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose).. The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups.. Bill & Melinda Gates Foundation.

Topics: Adolescent; Adult; Africa; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Asia; Child; Child, Preschool; Clinical Trials as Topic; DNA, Protozoan; Dose-Response Relationship, Drug; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Treatment Outcome; Young Adult

The World Health Organization (WHO) recommends Artemisinin-based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision-making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin-piperaquine (DHA-P) versus other recommended ACTs.. To evaluate the effectiveness and safety of DHA-P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children.. We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013.. Randomized controlled trials comparing a three-day course of DHA-P to a three-day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria.. Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.. We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women. DHA-P versus artemether-lumefantrineIn Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA-P (PCR-adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).Compared to artemether-lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence). DHA-P versus artesunate plus mefloquineIn Asia, over 28 days follow-up, DHA-P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR-unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials (PCR-adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent benefit in preventing new infections has been seen over 63 days follow-up (PCR-unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR-unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR-adjusted treatment failure: one trial, 435 participants, low quality evidence).DHA-P is as. In Africa, dihydroartemisinin-piperaquine reduces overall treatment failure compared to artemether-lumefantrine, although both drugs have PCR-adjusted failure rates of less than 5%. In Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Mefloquine; Parasitemia; Quinolines; Randomized Controlled Trials as Topic

While significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Trophozoites

To review the pharmacology, pharmacokinetics, safety, and efficacy of artemether-lumefantrine for the treatment of Plasmodium falciparum malaria.. English-language articles indexed in PubMed (1947-November 2011) were identified, using the search terms artemether-lumefantrine, artemether-lumefantrine AND malaria, Coartem, and Coartem AND malaria.. Available English-language articles were reviewed. In addition, the malaria treatment regimens recommended by region as provided by the World Health Organization and the treatment guidelines from the Centers for Disease Control and Prevention were reviewed.. Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria. The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. In the reviewed studies, the polymerase chain reaction (PCR)-corrected 28-day cure rates of artemether-lumefantrine were noninferior to the most common comparators, including chloroquine, dapsone, and other artemisinin derivatives (86-100% vs 51-100%, respectively). PCR-corrected day-42 cure rates were 92-99.3% for artemether-lumefantrine versus 62-100% for the comparator groups. The major adverse effects (gastrointestinal and central nervous system) were mild to moderate in severity and did not require a change in therapy. Although adherence to artemether-lumefantrine has been described as a potential problem due to the complicated dosing schedule, studies have described clinical cure rates similar to those of other antimalarials.. Artemether-lumefantrine is a safe and effective treatment for children and adults with P. falciparum malaria.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Administration Schedule; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Medication Adherence; Plasmodium falciparum; Polymerase Chain Reaction

Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Infectious; Pyrimethamine; Quinine; Sulfadoxine; Treatment Outcome

To prevent the development of drug resistance, the World Health Organization (WHO) recommends treating malaria with combination therapy. Azithromycin, an antibiotic with antimalarial properties, may be a useful additional option for antimalarial therapy.. To compare the use of azithromycin alone or in combination with other antimalarial drugs with the use of alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax.. We searched the Cochrane Infectious Diseases Group Specialized Register (August 2010); CENTRAL (The Cochrane Library Issue 3, 2010); MEDLINE (1966 to August 2010); EMBASE (1974 to August 2010); LILACS (August 2010); the metaRegister of Controlled Trials (mRCT, August 2010); conference proceedings; and reference lists. We also contacted researchers and a pharmaceutical company.. Randomized controlled trials comparing azithromycin, either alone or combined with another antimalarial drug, with another antimalarial drug used alone or combined with another antimalarial drug, or with azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin were used. The primary outcome was treatment failure by day 28, defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. Secondary outcomes included treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), fever and parasite clearance time, and adverse events.. Two people independently applied the inclusion criteria, extracted data and assessed methodological quality. We used risk ratio (RR) and 95% confidence intervals (CI).. Fifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax.Three-day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52).Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83).. Currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycin's future for the treatment of malaria does not look promising.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Atovaquone; Azithromycin; Chloroquine; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Mefloquine; Proguanil; Pyrimethamine; Randomized Controlled Trials as Topic; Sulfadoxine; Treatment Failure

Randomized trials have confirmed the efficacy and safety of artemether-lumefantrine (AL) for treatment of uncomplicated Plasmodium falciparum malaria. Data from seven studies supported by Novartis (1996-2007), including 647 adults (> 16 years of age, 83.3% completed the study) and 1,332 children (≤ 16 years of age, 89.3% completed the study) with microscopically confirmed uncomplicated P. falciparum malaria and treated with the recommended regimen of AL, were pooled. The 28-day polymerase chain reaction-corrected parasitologic cure rate (primary efficacy endpoint) was 97.1% (495 of 510) in adults and 97.3% (792 of 814) in children (evaluable population). Gametocytemia prevalence after day was 4.2% (23 of 554) in adults and 0.9% (8 of 846) in children. No noteworthy safety signals were observed. Serious adverse events occurred in 1.4% of the adults and 1.3% of the children. This study is the largest data set to date assessing AL therapy for treatment of acute uncomplicated P. falciparum malaria. Artemether-lumefantrine showed high cure rates and rapid resolution of parasitemia, fever, and gametocytemia in adults and children, and showed an excellent safety and tolerability profile.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Young Adult

Artemether-lumefantrine (AL; Coartem, Riamet) is the first fixed-dose artemisinin combination therapy (ACT) regimen to be manufactured under Good Manufacturing Practice conditions, and is the most widely adopted ACT regimen used in malaria control programs. AL is approved for the treatment of uncomplicated malaria in adults, children and infants, and as treatment of uncomplicated malaria in nonimmune travelers returning from malarious areas. AL is efficacious for treating uncomplicated malaria in children and the frequency of associated adverse events is not higher than other available ACT regimens. In this review, available evidence on efficacy and safety of AL in the treatment of uncomplicated malaria, with emphasis on children where appropriate, and focusing on characteristics that are potentially important for malaria control policy decisions, are presented and discussed.

Topics: Administration, Oral; Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Plasmodium falciparum; Treatment Outcome

A fixed-dose combination of artemether-lumefantrine (AL, Coartem(R)) has shown high efficacy, good tolerability and cost-effectiveness in adults and children with uncomplicated malaria caused by Plasmodium falciparum. Lumefantrine bioavailability is enhanced by food, particularly fat.As the fat content of sub-Saharan African meals is approximately a third that of Western countries, it raises the question of whether fat consumption by African patients is sufficient for good efficacy. Data from healthy volunteers have indicated that drinking 36 mL soya milk (containing only 1.2 g of fat) results in 90% of the lumefantrine absorption obtained with 500 mL milk (16 g fat). African diets are typically based on a carbohydrate staple (starchy root vegetables, fruit [plantain] or cereals) supplemented by soups, relishes and sauces derived from vegetables, pulses, nuts or fish. The most important sources of dietary fat in African countries are oil crops (e.g. peanuts, soya beans) and cooking oils as red palm, peanut, coconut and sesame oils. Total fat intake in the majority of subSaharan countries is estimated to be in the range 30-60 g/person/day across the whole population (average 43 g/person/day). Breast-feeding of infants up to two years of age is standard, with one study estimating a fat intake of 15-30 g fat/day from breast milk up to the age of 18 months. Weaning foods typically contain low levels of fat, and the transition from breast milk to complete weaning is associated with a marked reduction in dietary fat. Nevertheless, fat intake >10 g/day has been reported in young children post-weaning. A randomized trial in Uganda reported no difference in the efficacy of AL between patients receiving supervised meals with a fixed fat content (~23 g fat) or taking AL unsupervised, suggesting that fat intake at home was sufficient for optimal efficacy. Moreover, randomized trials in African children aged 5-59 months have shown similar high cure rates to those observed in older populations, indicating that food consumption is adequate post-weaning. In conclusion, it appears that only a very small amount of dietary fat is necessary to ensure optimal efficacy with AL and that the fat content of standard meals or breast milk in sub-Saharan Africa is adequate.

Topics: Adult; Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Diet; Dietary Fats; Drug Combinations; Ethanolamines; Feeding Behavior; Fluorenes; Food-Drug Interactions; Humans; Infant; Malaria, Falciparum; Randomized Controlled Trials as Topic

The World Health Organization recommends artemether-lumefantrine, an expensive drug, as a treatment for uncomplicated malaria. We sought evidence of the superiority of the four-dose regimen over existing treatments.. To evaluate the four-dose regimen of artemether-lumefantrine for treating uncomplicated falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register (October 2005), CENTRAL (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to October 2005), EMBASE (1988 to October 2005), LILACS (1982 to October 2005), conference proceedings, and reference lists of articles. We also contacted experts in malaria research and the pharmaceutical company that manufactures artemether-lumefantrine.. Randomized controlled trials comparing four doses of artemether-lumefantrine with standard treatment regimens (single drug or combination), or six doses of artemether-lumefantrine, for treating uncomplicated falciparum malaria.. Two authors independently applied inclusion criteria to potentially relevant trials, assessed trial quality, and extracted data, including adverse events. Total failure by day 28 (day 42 for sulfadoxine-pyrimethamine and day 63 for mefloquine) was the primary outcome.. Seven trials (2057 participants) tested a four-dose regimen. More people tended to fail treatment with artemether-lumefantrine than with other drugs, including sulfadoxine-pyrimethamine (247 participants, 1 trial), halofantrine (86 participants, 1 trial), and mefloquine (233 participants, 1 trial; difference statistically significant for mefloquine). When compared with chloroquine, artemether-lumefantrine was better in two trials (378 participants), but over 50% of the participants treated with chloroquine had total failure by day 28. Fewer people failed treatment with the six-dose regimen compared to the four-dose regimen (RR 7.71, 95% CI 2.99 to 19.88; 306 participants, 1 trial).. The four-dose regimen of artemether-lumefantrine seems to be less effective than regimens against which it has been tested. The six-dose regimen is superior to four-dose regimen.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Randomized Controlled Trials as Topic; Sesquiterpenes; Treatment Failure

To demonstrate the superiority of the six-dose over the four-dose regimen of artemether-lumefantrine (co-artemether, Coartem) in patients >12 years, data from 11 randomized clinical trials were pooled and analyzed. A total of 1368 patients with uncomplicated Plasmodium falciparum malaria (six-dose: 598; four-dose: 770) were included in the analysis, together with 717 patients treated with comparators. Analysis of the 28-day cure rate based on the ITT and evaluable populations yielded corrected cure rates for the six-dose regimen of 87% and 97% compared with 74% and 87%, respectively, with the four-dose regimen (P<0.0001, for both comparisons). For mefloquine/artesunate, the most frequently used comparator, cure rates were 87% and 99%, respectively. The six-dose regimen was well tolerated and not markedly different to the four-dose regimen. The main finding of our analysis is that the six-dose regimen of co-artemether is more effective than the four-dose regimen in adolescents and adults without compromising safety.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Randomized Controlled Trials as Topic; Sesquiterpenes; Treatment Outcome

The World Health Organization recommends artemether-lumefantrine for treating uncomplicated malaria. We sought evidence of superiority of the six-dose regimen over existing treatment regimens as well as its effectiveness in clinical situations.. To evaluate the six-dose regimen of artemether-lumefantrine for treating uncomplicated falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register (April 2005), CENTRAL (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to April 2005), EMBASE (1974 to April 2005), LILACS (1982 to April 2005), conference proceedings, and reference lists of articles. We also contacted experts in malaria research and the pharmaceutical company that manufactures artemether-lumefantrine.. Randomized controlled trials comparing six doses of artemether-lumefantrine administered orally with standard treatment regimens (single drug or combination), or supervised with unsupervised treatment, for uncomplicated falciparum malaria.. Two authors independently applied inclusion criteria to potentially relevant trials, assessed trial quality, and extracted data, including adverse events. Total failure by day 28 (day 42 for sulfadoxine-pyrimethamine and day 63 for mefloquine) was the primary outcome.. Nine trials (4547 participants) tested the six-dose regimen. Total failure at day 28 for artemether-lumefantrine was lower when compared with amodiaquine (270 participants, 1 trial), amodiaquine plus sulfadoxine-pyrimethamine (507 participants, 1 trial), but not with chloroquine plus sulfadoxine-pyrimethamine (201 participants, 2 trials). In comparisons with artemisinin derivative combinations, artemether-lumefantrine performed better than amodiaquine plus artesunate (668 participants, 2 trials), worse than mefloquine plus artesunate (270 participants, 4 trials), and no differently to dihydroartemisinin-napthoquine-trimethoprim (89 participants, 1 trial).. The six-dose regimen of artemether-lumefantrine appears more effective than antimalarial regimens not containing artemisinin derivatives.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Randomized Controlled Trials as Topic; Sesquiterpenes

Artemether-lumefantrine is being promoted by the World Health Organization for treating uncomplicated malaria. It is expensive. We sought evidence of its superiority over existing treatment regimens.. To compare artemether-lumefantrine with other antimalarial drugs for treating uncomplicated falciparum malaria.. We searched the Cochrane Infectious Diseases Group specialized trials register (April 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE (1966 to April 2002), EMBASE (1988 to April 2002), conference proceedings, and reference lists of articles. We contacted experts in malaria research and the pharmaceutical company that manufactures artemether-lumefantrine.. Randomized and quasi-randomized trials comparing artemether-lumefantrine administered orally with standard treatment regimens (single drug or combination).. Two reviewers independently applied inclusion criteria to potentially relevant trials, assessed trial quality, and extracted data. Parasitaemia on day 28 (day 42 for sulfadoxine-pyrimethamine and day 63 for mefloquine) was the primary outcome. Adverse event information was collected from the studies.. Eight trials (2117 participants) met the inclusion criteria. In the four studies against single agents, failure rates for artemether-lumefantrine tended to be higher in comparisons against sulfadoxine-pyrimethamine, halofantrine, and mefloquine. This difference was statistically significant for mefloquine. When compared with chloroquine, artemether-lumefantrine was better in two studies, but the failure rate for chloroquine at these sites was over 50%. All single agent studies used four doses of artemether-lumefantrine. In comparisons against combination treatment, three trials tested artemether-lumefantrine against mefloquine-artesunate and showed that artemether-lumefantrine was inferior for day 28 cure (Relative Risk 6.33, 95% confidence interval 3.08 to 13.01). If this comparison is confined to the two trials where participants received six doses, artemether-lumefantrine was associated with higher cure rates, but this was not statistically significant (Relative Risk 4.20, 95% confidence interval 0.55 to 31.93).. Artemether-lumefantrine is more effective than chloroquine in chloroquine resistant areas. Artemether-lumefantrine is less effective than mefloquine or mefloquine combined with artesunate. We found no evidence to confirm or refute whether artemether-lumefantrine was better than sulfadoxine-pyrimethamine.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Randomized Controlled Trials as Topic; Sesquiterpenes

Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy in Sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks.. We conducted a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of extended duration AL in children with malaria in high-transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin, and lumefantrine over 42-day clinical follow-up. Primary outcomes were (1) comparative pharmacokinetic parameters between regimens and (2) recurrent parasitemia analyzed as intention-to-treat.. A total of 177 children aged 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (P < .001). A predefined day 7 lumefantrine threshold of 280 ng/mL was strongly predictive of recurrence risk at 28 and 42 days (P < .001). Kaplan-Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3- and 5-day regimens. No significant toxicity was seen with the extended regimen.. Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high-transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk, and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen.. ClinicalTrials.gov number NCT03453840.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Malaria, Falciparum; Parasitemia; Prospective Studies; Reinfection; Uganda

Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia.. We conducted an open-label, individually randomised controlled trial in Cambodia, which recruited participants aged 16-65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether-lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomisation schedule, and randomisation was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1-28, 29-56, or 57-84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete.. Between March 11 and Nov 20, 2020, 1480 individuals were enrolled, of whom 738 were randomly assigned to artemether-lumefantrine and 742 to the multivitamin. 713 participants in the artemether-lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2-4) of 713 participants had parasitaemia or clinical malaria in the artemether-lumefantrine group and 123 (17%, 15-20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12-18; p<0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P vivax were 18 (3%, 95% CI 2-4) in the artemether-lumefantrine group versus 112 (16%, 13-19) in the multivitamin group (absolute risk difference 13%, 95% CI 10-16; p<0·0001). The numbers of participants with P falciparum were two (0·3%, 95% CI 0·03-1·01) in the artemether-lumefantrine group versus 12 (1·7%, 0·9-2·9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0·4-2·4; p=0·013). Overall reported adherence to the full course of medication was 97% (95% CI 96-98; 1797 completed courses out of 1854 courses started) in the artemether-lumefantrine group and 98% (97-98; 1842 completed courses in 1885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1·9% (355 events in 18 806 doses) in the artemether-lumefantrine group and 1·1% (207 events in 19 132 doses) in the multivitamin group (p<0·0001).. Antimalarial chemoprophylaxis with artemether-lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion.. The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Cambodia; Chemoprevention; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum

WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo.. We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants.. Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97).. Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa.. UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Democratic Republic of the Congo; Female; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Primaquine; Uganda; World Health Organization

When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response.. Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm. 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008).. Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malawi; Treatment Outcome

We aimed to assess safety, tolerability, and Plasmodium vivax relapse rates of ultra-short course (3.5 days) high-dose (1 mg/kg twice daily) primaquine (PQ) for uncomplicated malaria because of any Plasmodium species in children randomized to early- or delayed treatment.. Children aged 0.5 to 12 years with normal glucose-6-phosphate-dehydrogenase (G6PD) activity were enrolled. After artemether-lumefantrine (AL) treatment, children were randomized to receive PQ immediately after (early) or 21 days later (delayed). Primary and secondary endpoints were the appearance of any P. vivax parasitemia within 42 or 84 days, respectively. A non-inferiority margin of 15% was applied (ACTRN12620000855921).. A total of 219 children were recruited, 70% with Plasmodium falciparum and 24% with P. vivax. Abdominal pain (3.7% vs 20.9%, P <0.0001) and vomiting (0.9% vs 9.1%, P = 0.01) were more common in the early group. At day 42, P. vivax parasitemia was observed in 14 (13.2%) and 8 (7.8%) in the early and delayed groups, respectively (difference, -5.4%; 95% confidence interval -13.7 to 2.8). At day 84, P. vivax parasitemia was observed in 36 (34.3%) and 17 (17.5%; difference -16.8%, -28.6 to -6.1).. Ultra-short high-dose PQ was safe and tolerated without severe adverse events. Early treatment was non-inferior to delayed treatment in preventing P. vivax infection at day 42.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Parasitemia; Plasmodium vivax; Primaquine; Time-to-Treatment

This study examined the treatment response of mixed vs single-species Plasmodium falciparum infections to artemisinin-based combination therapies (ACTs).. A total of 1211 blood samples collected on days 0, 7, 14, 21, 28, 35, and 42 from 173 individuals enrolled in two randomized ACT efficacy studies were tested for malaria using 18s ribosomal RNA-based real-time polymerase chain reaction. All recurrent parasitemia were characterized for Plasmodium species composition and time to reinfection during 42-day follow-up compared across ACTs.. Day 0 samples had 71.1% (116/163) single P. falciparum infections and 28.2% (46/163) coinfections. A total of 54.0% (88/163) of individuals tested positive for Plasmodium at least once between days 7-42. A total of 19.3% (17/88) of individuals with recurrent infections were infected with a different Plasmodium species than observed at day 0, with 76.5% (13/17) of these "hidden" infections appearing after clearing P. falciparum present at day 0. Artesunate-mefloquine (16.4 hours) and dihydroartemisinin-piperaquine (17.6 hours) had increased clearance rates over artemether-lumefantrine (21.0 hours). Dihydroartemisinin-piperaquine exhibited the longest duration of reinfection prophylaxis. Cure rates were comparable across each species composition.. No differences in clearance rates were found depending on whether the infection contained species other than P. falciparum. Significantly longer durations of protection were observed for individuals treated with dihydroartemisinin-piperaquine.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Humans; Kenya; Malaria; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Reinfection; Retrospective Studies

In Nigeria, declining responsiveness to artemether-lumefantrine (AL), the artemisinin-based combination therapy (ACT) of choice since 2005, has been reported. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently prequalified by the WHO for the treatment of uncomplicated falciparum malaria. However, PA data from the Nigerian pediatric population is scarce. Therefore, the efficacy and safety of PA and AL using the WHO 28-day anti-malarial therapeutic efficacy study protocol in Ibadan, southwest Nigeria, were compared.. In an open-labelled, randomized, controlled clinical trial, 172 children aged 3-144 months with a history of fever and microscopically confirmed uncomplicated Plasmodium falciparum malaria were enrolled in southwest Nigeria. Enrollees were randomly assigned to receive PA or AL at standard dosages according to body weight for 3 days. Venous blood was obtained for hematology, blood chemistry, and liver function tests on days 0, 3, 7, and 28 as part of the safety evaluation.. 165 (95.9%) of the enrolled individuals completed the study. About half (52.3%; 90/172) of enrollees were male. Eighty-seven (50.6%) received AL, while 85 (49.4%) received PA. Day 28, adequate clinical and parasitological response for PA was 92.7% [(76/82) 95% CI 83.1, 95.9] and 71.1% [(59/83) 95% CI 60.4, 79.9] for AL (0.001). Fever and parasite clearance were similar in both groups. Two of six and eight of 24 parasite recurrences were observed among PA- and AL-treated children, respectively. PCR-corrected Day-28 cure rates for PA were 97.4% (76/78) and 88.1% (59/67) for AL (= 0.04) in the per-protocol population after new infections were censored. Hematological recovery at day 28 was significantly better among PA-treated patients (34.9% 2.8) compared to those treated with AL (33.1% 3.0) (0.002). Adverse events in both treatment arms were mild and similar to the symptoms of malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise.. PA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria.. Clinicaltrials.gov: NCT05192265.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Retrospective Studies; Treatment Outcome

Malaria is a major public health problem in Madagascar, particularly in coastal areas. We conducted a randomized, controlled, parallel-group study of artemisinin-based combination therapy (ACT) in Mananjary and Farafangana, two localities on the rainy south-east coast of Madagascar, from March to September 2018. The efficacy and safety of artesunate + amodiaquine (ASAQ) and artemether + lumefantrine (AL) were assessed according to the WHO protocol with a 28-day follow-up. Children aged 6 months to 14 years with uncomplicated Plasmodium falciparum malaria were randomized to receive ASAQ or AL for three days (1:1). 347/352 (98.5%) randomized patients reached the study endpoint on day 28. Crude adequate clinical and parasitological response (ACPR) rates were 100% (95% CI: 98.8-100%) in the ASAQ group and 96% (95% CI: 93.1-98.9%) in the AL group (per protocol population). However, the PCR-corrected ACPR rate was 97.7% (95% CI: 95.4-100%) in the AL group. Two cases of recrudescence and three of re-infection were observed. Mild and moderate adverse events, including gastrointestinal and/or nervous disorders, were reported in 11.9% (42/352) of patients. We found that ASAQ and AL were safe and efficacious for treating uncomplicated P. falciparum malaria. They may be used for treatment at health facilities and at the community level, and for mass drug administration campaigns.. Efficacité thérapeutique et sécurité de l’artésunate + amodiaquine et de l’artéméther + luméfantrine pour le traitement du paludisme simple à Plasmodium falciparum chez les enfants sur la côte sud-est pluvieuse de Madagascar.. Le paludisme demeure un problème majeur de santé publique à Madagascar notamment dans les régions côtières. Nous avons réalisé une étude multisite, randomisée, contrôlée, en groupes parallèles sur la combinaison thérapeutique à base des dérivés d’artémisinine (CTA) à Mananjary et Farafangana, deux localités sur la côte sud-est pluvieuse de Madagascar, de mars au septembre 2018. L’efficacité et la sécurité de l’artésunate + amodiaquine (ASAQ) et de l’artéméther + luméfantrine (AL) ont été évaluées selon le protocole de l’OMS avec un suivi de 28 jours. Des enfants âgés de 6 mois à 14 ans souffrant de paludisme non compliqué à Plasmodium falciparum ont été randomisés (1:1) pour recevoir ASAQ ou AL pendant trois jours. 347/352 (98,5 %) des patients randomisés ont pu être suivis jusqu’au jour 28. Le taux de réponse clinique et parasitologique adéquate (RCPA) était de 100 % (95 % CI : 98,8 – 100 %) dans le bras thérapeutique ASAQ et de 96 % (95 % CI : 93,1 – 98,9 %) dans le bras thérapeutique AL (population per protocole). Cependant, après correction par PCR, le taux de RCPA était de 97,7 % (95 % CI : 95,4 – 100 %) dans le bras thérapeutique AL. Deux cas de recrudescence et trois cas de réinfections ont été observées. Des effets indésirables légers et modérés, notamment des troubles gastro-intestinaux et/ou nerveux, ont été rapportés chez 11,9 % (42/352) des patients. Nos résultats démontrent que l’ASAQ et l’AL sont sûrs et efficaces pour le traitement du paludisme non compliqué à P. falciparum. Ces deux CTA peuvent par conséquent être utilisés pour traiter le paludisme dans les centres de santé et au niveau communautaire, et aussi pendant les campagnes de traitement de masse.

Topics: Amodiaquine; Artemether, Lumefantrine Drug Combination; Artesunate; Child; Humans; Madagascar; Malaria, Falciparum

Malaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective; the most used being artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Pyronaridine-artesunate (PA) is a new artemisinin-based combination. The main objective of this study is to determine the efficacy and safety of PA versus AL or DP when administered to pregnant women with confirmed. A phase 3, non-inferiority, randomised, open-label clinical trial to determine the safety and efficacy of AL, DP and PA in pregnant women with malaria in five sub-Saharan, malaria-endemic countries (Burkina Faso, Democratic Republic of the Congo, Mali, Mozambique and the Gambia). A total of 1875 pregnant women will be randomised to one of the treatment arms. Women will be actively monitored until Day 63 post-treatment, at delivery and 4-6 weeks after delivery, and infants' health will be checked on their first birthday. The primary endpoint is the PCR-adjusted rate of adequate clinical and parasitological response at Day 42 in the per-protocol population.. This protocol has been approved by the Ethics Committee for Health Research in Burkina Faso, the National Health Ethics Committee in the Democratic Republic of Congo, the Ethics Committee of the Faculty of Medicine and Odontostomatology/Faculty of Pharmacy in Mali, the Gambia Government/MRCG Joint Ethics Committee and the National Bioethics Committee for Health in Mozambique. Written informed consent will be obtained from each individual prior to her participation in the study. The results will be published in peer-reviewed open access journals and presented at (inter)national conferences and meetings.. PACTR202011812241529.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Clinical Trials, Phase III as Topic; Drug Combinations; Female; Humans; Infant; Malaria; Malaria, Falciparum; Pregnancy; Pregnant Women; Randomized Controlled Trials as Topic; Sub-Saharan African People; Treatment Outcome

Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.. This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.. One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).. In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.. The trial is registered at ISRCTN 11594437.

Topics: alpha-Thalassemia; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Female; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Primaquine

In areas co-endemic for Plasmodium vivax and Plasmodium falciparum there is an increased risk of P vivax parasitaemia following P falciparum malaria. Radical cure is currently only recommended for patients presenting with P vivax malaria. Expanding the indication for radical cure to patients presenting with P falciparum malaria could reduce their risk of subsequent P vivax parasitaemia.. We did a multicentre, open-label, superiority randomised controlled trial in five health clinics in Bangladesh, Indonesia, and Ethiopia. In Bangladesh and Indonesia, patients were excluded if they were younger than 1 year, whereas in Ethiopia patients were excluded if they were younger than 18 years. Patients with uncomplicated P falciparum monoinfection who had fever or a history of fever in the 48 h preceding clinic visit were eligible for enrolment and were required to have a glucose-6-dehydrogenase (G6PD) activity of 70% or greater. Patients received blood schizontocidal treatment (artemether-lumefantrine in Ethiopia and Bangladesh and dihydroartemisinin-piperaquine in Indonesia) and were randomly assigned (1:1) to receive either high-dose short-course oral primaquine (intervention arm; total dose 7 mg/kg over 7 days) or standard care (standard care arm; single dose oral primaquine of 0·25 mg/kg). Random assignment was done by an independent statistician in blocks of eight by use of sealed envelopes. All randomly assigned and eligible patients were included in the primary and safety analyses. The per-protocol analysis excluded those who did not complete treatment or had substantial protocol violations. The primary endpoint was the incidence risk of P vivax parasitaemia on day 63. This trial is registered at ClinicalTrials.gov, NCT03916003.. Between Aug 18, 2019, and March 14, 2022, a total of 500 patients were enrolled and randomly assigned, and 495 eligible patients were included in the intention-to-treat analysis (246 intervention and 249 control). The incidence risk of P vivax parasitaemia at day 63 was 11·0% (95% CI 7·5-15·9) in the standard care arm compared with 2·5% (1·0-5·9) in the intervention arm (hazard ratio 0·20, 95% CI 0·08-0·51; p=0·0009). The effect size differed with blood schizontocidal treatment and site. Routine symptom reporting on day 2 and day 7 were similar between groups. In the first 42 days, there were a total of four primaquine-related adverse events reported in the standard care arm and 26 in the intervention arm; 132 (92%) of all 143 adverse events were mild. There were two serious adverse events in the intervention arm, which were considered unrelated to the study drug. None of the patients developed severe anaemia (defined as haemoglobin <5 g/dL).. In patients with a G6PD activity of 70% or greater, high-dose short-course primaquine was safe and relatively well tolerated and reduced the risk of subsequent P vivax parasitaemia within 63 days by five fold. Universal radical cure therefore potentially offers substantial clinical, public health, and operational benefits, but these benefits will vary with endemic setting.. Australian Academy of Science Regional Collaborations Program, Bill & Melinda Gates Foundation, and National Health and Medical Research Council.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Australia; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Parasitemia; Plasmodium falciparum; Plasmodium vivax; Primaquine

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Nitriles; Pyrazoles; Pyrimidines; Single-Blind Method; Young Adult

The World Health Organization recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available. The efficacy of quinine plus clindamycin was compared with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age.. An open-label, phase 3, randomized trial was conducted in western Kenya. Children aged 6-59 months with uncomplicated falciparum malaria were randomly assigned (1:1) via a computer-generated randomization list to receive 3 days of twice a day treatment with either oral quinine (20 mg/kg/day) plus clindamycin (20 mg/kg/day) or artemether-lumefantrine (artemether 20 mg, lumefantrine 120 mg) as one (for those weighing 5-14 kg) or two (for those weighing 15-24 kg) tablets per dose. The primary outcome was a PCR-corrected rate of adequate clinical and parasitological response (ACPR) on day 28 in the per-protocol population.. Of the 384 children enrolled, 182/192 (94.8%) receiving quinine plus clindamycin and 171/192 (89.1%) receiving artemether-lumefantrine completed the study. The PCR-corrected ACPR rate was 44.0% (80 children) in the quinine plus clindamycin group and 97.1% (166 children) in the artemether-lumefantrine group (treatment difference - 53.1%, 95% CI - 43.5% to - 62.7%). At 72 h after starting treatment, 50.3% (94 children) in the quinine plus clindamycin group were still parasitaemic compared with 0.5% (1 child) in the artemether-lumefantrine group. Three cases of severe malaria were recorded as serious adverse events in the quinine plus clindamycin group.. The study found no evidence to support the use of a 3-day low dose course of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective.. This trial is registered with the Pan-African Clinical Trials Registry, PACTR20129000419241.

Topics: Artemether, Lumefantrine Drug Combination; Child, Preschool; Clindamycin; Drug Therapy, Combination; Female; Humans; Infant; Kenya; Malaria, Falciparum; Male; Quinine

Many studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cameroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6-120 months in Yaoundé, Cameroon.. A two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasitological response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.. A total of 242 children were randomized to receive AS-AQ (n = 114) and AL (n = 128). The PP PCR adjusted day 28 cure rates were [AS-AQ = 96.9% (95% CI, 91.2-99.4) versus AL = 95.5% (95% CI, 89.9-98.5), P = 0.797]. Expected mild to moderate adverse events were reported in both arms [AS-AQ = 83 (84.7%) versus AL = 99 (86.1%), P = 0.774]. The most common adverse events included: transient changes of hematologic indices and fever.. This study demonstrated that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé. The evidence from this study supports the parallel use of the two drugs in routine practice. However, the findings from this study do not describe the likely duration of antimalarial effectiveness in holoendemic areas where multiple courses of treatment might be required.. This study is a randomized controlled trial and it was retrospectively registered on 23/09/2020 at ClinicalTrials.gov with registration number NCT04565184.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Cameroon; Child; Drug Combinations; Ethanolamines; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Treatment Outcome

Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether-lumefantrine could provide an efficacious treatment for multidrug-resistant infections.. We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2-65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether-lumefantrine alone (dosed according to WHO guidelines) or artemether-lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664).. Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether-lumefantrine alone and 156 received artemether-lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92-99) of 156 patients with artemether-lumefantrine plus amodiaquine versus 146 (95%, 89-97) of 154 patients with artemether-lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2-1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether-lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether-lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14-1·40, p=0·17). Artemether-lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1-2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether-lumefantrine alone (vomiting, 12 [8%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether-lumefantrine alone versus five (3%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether-lumefantrine alone and 95 (61%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·0001.. Artemether-lumefantrine plus amodiaquine provides an alternative to artemether-lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether-lumefantrine in malaria-endemic populations.. Bill & Melinda Gates Foundation, Wellcome Trust.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Recurrence; Vomiting

Malaria significantly rebounded in 2018 in the Comoros; this created an urgent need to conduct clinical trials to investigate the effectiveness of artemisinin and its derivatives.. An open-label, non-randomised controlled trial of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) was conducted in Grande Comore island from June 2019 to January 2020. A total of 238 uncomplicated falciparum malaria cases were enrolled and divided 1:1 into two treatments. The primary endpoint was the 42-day adequate clinical and parasitological responses (ACPR). Secondary endpoints were parasitaemia and fever clearance at day 3, gametocytes and tolerability.. The 42-day ACPR before and after PCR correction were 91.43% (95% CI 83.93-95.76%) and 98.06% (95% CI 92.48-99.66%) for AP treatment, respectively, and 96.00% (95% CI 88.17-98.14%) and 98.97% (95% CI 93.58-99.95%) for AL treatment, respectively. Complete clearance of the parasitaemia and fever for both groups was detected on day 3. Gametocytes disappeared on day 21 in the AP group and on day 2 in AL group. Specifically, the adverse reactions were mild in both groups.. It was found that AP and AL maintained their high efficacy and tolerance in the Comoros. Nonetheless, asymptomatic malaria infections bring new challenges to malaria control.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria; Malaria, Falciparum; Piperazines; Plasmodium falciparum; Quinolines

Antimalarial chemoprophylaxis for high risk groups in endemic areas of Southeast Asia has the potential to reduce malaria transmission and accelerate elimination. However, the optimal choice of medication and dosing for many potential candidates is not clear. For a planned randomised controlled trial of prophylaxis for forest goers in Cambodia, artemether-lumefantrine (AL) was selected because of its ongoing efficacy and excellent tolerability and safety. As AL had not been used before for this purpose, a previously published pooled pharmacometric meta-model was used to determine the optimal dosing schedule.. A full 3 day AL treatment course given twice a month, and twice daily treatment given once a week, resulted in trough concentrations consistently above the therapeutic threshold of 200 ng/mL. However, the most favourable exposure profile, and arguably most practical dosing scenario, was an initial 3 day full AL treatment course followed by twice daily dosing given once a week for the duration of chemoprevention. The latter was adopted as the dosing schedule for the trial.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Chemoprevention; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria; Malaria, Falciparum

Urogenital schistosomiasis is prevalent in many malaria endemic regions of sub-Saharan Africa and can lead to long-term health consequences if untreated. Antimalarial drugs used to treat uncomplicated malaria have shown to exert some activity against Schistosoma haematobium. Here, we explore the efficacy on concomitant urogenital schistosomiasis of first-line recommended artemisinin-based combination therapies (ACTs) and investigational second-generation ACTs when administered for the treatment of uncomplicated malaria in Gabon.. Microscopic determination of urogenital schistosomiasis was performed from urine samples collected from patients with confirmed uncomplicated malaria. Egg excretion reduction rate and cure rate were determined at 4-weeks and 6-weeks post-treatment with either artesunate-pyronaridine, artemether-lumefantrine, artesunate-amodiaquine or artefenomel-ferroquine.. Fifty-two (16%) out of 322 malaria patients were co-infected with urogenital schistosomiasis and were treated with antimalarial drug combinations. Schistosoma haematobium egg excretion rates showed a median reduction of 100% (interquartile range (IQR), 17% to 100%) and 65% (IQR, -133% to 100%) at 4-weeks and 6-weeks post-treatment, respectively, in the artesunate-pyronaridine group (n = 20) compared to 35% (IQR, -250% to 70%) and 65% (IQR, -65% to 79%) in the artemether-lumefantrine group (n = 18). Artesunate-amodiaquine (n = 2) and artefenomel-ferroquine combination (n = 3) were not able to reduce the rate of eggs excreted in this limited number of patients. In addition, cure rates were 56% and 37% at 4- and 6-weeks post-treatment, respectively, with artesunate-pyronaridine and no cases of cure were observed for the other antimalarial combinations.. Antimalarial treatments with artesunate-pyronaridine and artemether-lumefantrine reduced the excretion of S. haematobium eggs, comforting the hypothesis that antimalarial drugs could play a role in the control of schistosomiasis.. This trial is registered with clinicaltrials.gov, under the Identifier NCT04264130.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Drug Combinations; Ethanolamines; Gabon; Humans; Malaria; Malaria, Falciparum; Schistosomiasis haematobia

CIS43LS is a monoclonal antibody that was shown to protect against controlled. We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against. In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo.. CIS43LS was protective against

Topics: Adult; Antibodies, Monoclonal, Humanized; Antimalarials; Artemether, Lumefantrine Drug Combination; Headache; Humans; Malaria, Falciparum; Mali; Plasmodium falciparum

Gametocytes are the sexual stages ensuring continuity of the development cycle of the parasite, as well as its transmission to humans. The efficacy of artemisinin-based anti-malarials against asexual stages of Plasmodium has been reported in Madagascar, but their effects on gametocytes are not well documented. The present study aims to determine the emergence of gametocyte and gametocyte clearance after artesunate-amodiaquine (ASAQ) or artemether-lumefantrine (AL) treatment in children with uncomplicated Plasmodium falciparum malaria in 5 regions of Madagascar.. 558 children with uncomplicated P. falciparum malaria, aged between 1 and 15 years, were assigned randomly to AL or ASAQ treatment. They come from 5 regions of Madagascar with different epidemiological facies related to malaria: Ankilivalo, Benenitra, Ampanihy, Ankazomborona and Matanga. Gametocytes were identified by microscopy, from t blood smears at day 1, day 2, day 3, day 7, day 14, day 21 and day 28 after treatment.. At baseline, 9.7% (54/558) children [95% CI: 7.4-12.5%] had detectable gametocyte by microscopy. Among the 54 enrolled children, gametocytes emergence rate was high during the first days of treatment in both treatment arms (AL and ASAQ), especially on day 1. Gametocytes were undetectable from day 14 for AL arm while for ASAQ arm, gametocyte carriage was gradually decreased but persisted until day 21.. This study demonstrates that AL has a more rapid effect on gametocyte clearance compared to ASAQ in children with uncomplicated Plasmodium falciparum malaria.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Child; Child, Preschool; Drug Combinations; Ethanolamines; Humans; Infant; Madagascar; Malaria, Falciparum; Plasmodium falciparum

Routine monitoring of anti-malarial drugs is recommended for early detection of drug resistance and to inform national malaria treatment guidelines. In Ethiopia, the national treatment guidelines employ a species-specific approach. Artemether-lumefantrine (AL) and chloroquine (CQ) are the first-line schizonticidal treatments for Plasmodium falciparum and Plasmodium vivax, respectively. The National Malaria Control and Elimination Programme in Ethiopia is considering dihydroartemisinin-piperaquine (DHA/PPQ) as an alternative regimen for P. falciparum and P. vivax.. The study assessed the clinical and parasitological efficacy of AL, CQ, and DHA/PPQ in four arms. Patients over 6 months and less than 18 years of age with uncomplicated malaria mono-infection were recruited and allocated to AL against P. falciparum and CQ against P. vivax. Patients 18 years or older with uncomplicated malaria mono-infection were recruited and randomized to AL or dihydroartemisinin-piperaquine (DHA/PPQ) against P. falciparum and CQ or DHA/PPQ for P. vivax. Patients were followed up for 28 (for CQ and AL) or 42 days (for DHA/PPQ) according to the WHO recommendations. Polymerase chain reaction (PCR)-corrected and uncorrected estimates were analysed by Kaplan Meier survival analysis and per protocol methods.. A total of 379 patients were enroled in four arms (n = 106, AL-P. falciparum; n = 75, DHA/PPQ- P. falciparum; n = 142, CQ-P. vivax; n = 56, DHA/PPQ-P. vivax). High PCR-corrected adequate clinical and parasitological response (ACPR) rates were observed at the primary end points of 28 days for AL and CQ and 42 days for DHA/PPQ. ACPR rates were 100% in AL-Pf (95% CI: 96-100), 98% in CQ-P. vivax (95% CI: 95-100) at 28 days, and 100% in the DHA/PPQ arms for both P. falciparum and P. vivax at 42 days. For secondary endpoints, by day three 99% of AL-P. falciparum patients (n = 101) cleared parasites and 100% were afebrile. For all other arms, 100% of patients cleared parasites and were afebrile by day three. No serious adverse events were reported.. This study demonstrated high therapeutic efficacy for the anti-malarial drugs currently used by the malaria control programme in Ethiopia and provides information on the efficacy of DHA/PPQ for the treatment of P. falciparum and P. vivax as an alternative option.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Ethiopia; Humans; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax

In Southeast Asia, mutations in the Plasmodium falciparum K13 gene have led to delayed parasite clearance and treatment failures in patients with malaria receiving artemisinin combination therapies. Until recently, relevant K13 mutations had been mostly absent from Africa. Between 2018 and 2019, a phase 2 clinical study with 186 patients was conducted in Mali, Gabon, Ghana, Uganda, and Rwanda. Patients with malaria were randomized and treated with artemether-lumefantrine or cipargamin. Here we report an allele frequency of 22% for R561H in Rwanda and associated delayed parasite clearance. Notwithstanding, efficacy of artemether-lumefantrine remained high in Rwanda, with a 94.4% polymerase chain reaction-corrected cure rate.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Resistance; Gabon; Humans; Malaria, Falciparum; Mutation; Parasites; Plasmodium falciparum; Prevalence; Protozoan Proteins; Rwanda

Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere).. This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed.. All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional.. Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner.. ClinicalTrials.gov (NCT03334747).

Topics: Adult; Africa South of the Sahara; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Ethanolamines; Fluorenes; Humans; Indoles; Malaria, Falciparum; Plasmodium falciparum; Spiro Compounds; Treatment Outcome

Routine assessment of the efficacy of artemisinin-based combination therapies (ACTs) is critical for the early detection of antimalarial resistance. We evaluated the efficacy of ACTs recommended for treatment of uncomplicated malaria in five sites in Democratic Republic of the Congo (DRC): artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months with confirmed Plasmodium falciparum malaria were treated with one of the three ACTs and monitored. The primary endpoints were uncorrected and polymerase chain reaction (PCR)-corrected 28-day (AL and ASAQ) or 42-day (DP) cumulative efficacy. Molecular markers of resistance were investigated. Across the sites, uncorrected efficacy estimates ranged from 63% to 88% for AL, 73% to 100% for ASAQ, and 56% to 91% for DP. PCR-corrected efficacy estimates ranged from 86% to 98% for AL, 91% to 100% for ASAQ, and 84% to 100% for DP. No pfk13 mutations previously found to be associated with ACT resistance were observed. Statistically significant associations were found between certain pfmdr1 and pfcrt genotypes and treatment outcome. There is evidence of efficacy below the 90% cutoff recommended by WHO to consider a change in first-line treatment recommendations of two ACTs in one site not far from a monitoring site in Angola that has shown similar reduced efficacy for AL. Confirmation of these findings in future therapeutic efficacy monitoring in DRC is warranted.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Congo; Drug Combinations; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Piperazines; Plasmodium falciparum; Quinolines

In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy.. We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ) and dihydroartemisinin-piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment.. Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503; p < 0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: - 0.5045, 0.4469; p = 0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: - 0.0889, 0.3194; p = 0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154; p = 0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102; p = 0.004) for Poisson model.. We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes.. ClinicalTrials.gov: NCT00852423.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Female; Humans; Laboratories; Malaria, Falciparum; Pregnancy

Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of anti-malarial resistance.. Children aged six months to 14 years with uncomplicated falciparum malaria and a parasitaemia of 1000-100,000 parasites/µl determined by microscopy were enrolled from May-September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring anti-malarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms at their respective sites. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt and pfmdr1 genes were conducted.. Of 344 patients enrolled, 167/172 (97%) receiving ASAQ and 168/172 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100-100) and 95% (95% CI 91-100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97-100) in Ankazomborona and 83% (95% CI 76-92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100-100) and 98% (95% CI 95-100) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99-100) in Ankazomborona and 95% (95% CI 91-100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutation associated with artemisinin resistance was observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184 and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72-76.. PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. No genetic evidence of resistance to artemisinin was observed, which is consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Female; Humans; Infant; Madagascar; Malaria, Falciparum; Male; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Prevalence; Recurrence; Reinfection

Quinoline antimalarials cause drug-induced electrocardiographic QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria. Pregnant women with microscopy-confirmed parasitemia of any malaria species were enrolled in an open-label randomized controlled trial on the Thailand-Myanmar border from 2010 to 2016. Patients were randomized to the standard regimen of dihydroartemisinin-piperaquine (DP) or artesunate-mefloquine (ASMQ) or an extended regimen of artemether-lumefantrine (AL+). Recurrent

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Therapy, Combination; Electrocardiography; Female; Humans; Malaria; Malaria, Falciparum; Myanmar; Pregnancy; Pregnant Women; Quinolines; Thailand

In areas where malaria remains entrenched, novel transmission-reducing interventions are essential for malaria elimination. We report the impact screening-and-treatment of asymptomatic Malawian schoolchildren (n = 364 in the rainy season and 341 in the dry season) had on gametocyte-the parasite stage responsible for human-to-mosquito transmission-carriage. We used concomitant household-based surveys to predict the potential reduction in transmission in the surrounding community. Among 253 students with P. falciparum infections at screening, 179 (71%) had infections containing gametocytes detected by Pfs25 qRT-PCR. 84% of gametocyte-containing infections were detected by malaria rapid diagnostic test. While the gametocyte prevalence remained constant in untreated children, treatment with artemether-lumefantrine reduced the gametocyte prevalence (p < 0.0001) from 51.8 to 9.7% and geometric mean gametocyte density (p = 0.008) from 0.52 to 0.05 gametocytes/microliter. In community surveys, 46% of all gametocyte-containing infections were in school-age children, who comprised only 35% of the population. Based on these estimates six weeks after the intervention, the gametocyte burden in the community could be reduced by 25-55% depending on the season and the measure used to characterize gametocyte carriage. Thus, school-based interventions to treat asymptomatic infections may be a high-yield approach to not only improve the health of schoolchildren, but also decrease malaria transmission.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Cohort Studies; Female; Humans; Malaria, Falciparum; Malawi; Male; Mass Screening; Plasmodium falciparum; School Health Services

Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported.. Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL. DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area.. ClinicalTrials.gov identifier NCT01054248 , registered on 22 January 2010.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Mefloquine; Myanmar; Pregnancy; Premature Birth; Quinolines; Thailand

Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.. In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2-12 years and had an asexual parasitaemia of 5000-250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane-piperaquine, arterolane-piperaquine-mefloquine, or artemether-lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether-lumefantrine was administered twice daily (target dose 5-24 mg/kg of bodyweight of artemether and 29-144 mg/kg of bodyweight of lumefantrine), and oral arterolane-piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane-piperaquine-mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane-piperaquine-mefloquine versus artemether-lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was -7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.. Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane-piperaquine (n=73), arterolane-piperaquine-mefloquine (n=72), or artemether-lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane-piperaquine-mefloquine (100%, 95% CI 95-100; 72/72) was non-inferior to that after treatment with artemether-lumefantrine (96%, 95% CI 88-99; 69/72; risk difference 4%, 95% CI 0-9; p=0·25). The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine was non-inferior to that of arterolane-piperaquine (100%, 95% CI 95-100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane-piperaquine (5%, 95% CI 2-9; ten of 203 drug administrations; p=0·0013) or arterolane-piperaquine-mefloquine (5%, 3-9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether-lumefantrine (1%, 0-2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether-lumefantrine; n=19 for arterolane-piperaquine-mefloquine; n=23 for arterolane-piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.. This study shows that arterolane-piperaquine-mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.. UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries.

Topics: Administration, Oral; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Female; Heterocyclic Compounds, 1-Ring; Humans; Kenya; Malaria, Falciparum; Male; Mefloquine; Peroxides; Plasmodium falciparum; Quinolines; Spiro Compounds; Treatment Outcome

In the Greater Mekong Subregion, adults are at highest risk for malaria. The most relevant disease vectors bite during daytime and outdoors which makes forest work a high-risk activity for malaria. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria.. The protocol describes an open-label randomised controlled trial of artemether-lumefantrine (AL) versus multivitamin as prophylaxis against malaria among forest goers aged 16-65 years in rural northeast Cambodia. The primary objective is to compare the efficacy of the artemisinin combination therapy AL versus a multivitamin preparation as defined by the 28-day PCR parasite positivity rate and incidence of confirmed clinical malaria of any species. The sample size is 2200 patient-episodes of duration 1 month in each arm. The duration of follow-up and prophylaxis for each participant is 1, 2 or 3 consecutive 28-day periods, followed by a further 28 days of post-exposure prophylaxis, depending on whether they continue to visit the forest. Analysis will be done both by intention to treat and per protocol.. All participants will provide written, informed consent. Ethical approval was obtained from the Oxford Tropical Research Ethics Committee and the Cambodia National Ethics Committee for Health Research. Results will be disseminated by peer-reviewed open access publication together with open data.. NCT04041973; Pre-result.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cambodia; Forests; Humans; Malaria; Malaria, Falciparum; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Adult; Africa; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Female; Humans; Malaria, Falciparum; Pregnancy; Young Adult

Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso.. In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42.. Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05).. These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Burkina Faso; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Male; Mass Drug Administration; Plasmodium falciparum; Treatment Failure; Treatment Outcome

Primaquine is an important gametocytocidal drug that is combined with conventional malaria treatment for prevention of Plasmodium falciparum malaria transmission. Primaquine has been administered together on the first or the last day of conventional treatment but the impact of primaquine timing has never been examined. This study aimed to assess safety, efficacy and optimal timing of single full-dose (0.75 mg/kg) primaquine when added to a standard 6-dose regimen of artemether-lumefantrine (AL).. In an individual-level randomized controlled trial, enrolled participants who were G6PD normal and had uncomplicated P. falciparum malaria were randomly assigned to receive: AL only; AL and a single 0.75 mg/kg primaquine dose on the first day of AL (day 1); or AL and single 0.75 mg//kg primaquine on the last day of AL (day 3). On days 2, 3, 4, 8, 11 and 15, gametocytes were assessed and quantified by microscope and quantitative nuclear acid sequence based quantification (QT-NASBA).. Overall, 111 participants aged between 3 and 17 years were randomly allocated to receive AL only (36) or combined with primaquine on day 1 (38), or primaquine on day 3 (37). Day 4 gametocyte prevalence in AL + day 1 primaquine was half the level seen in either AL + day 3 primaquine or AL only arm (11% [4/35] vs 26% [8/31] and 27% [8/30], respectively) albeit not statistically significant. A similar trend of lower gametocyte in the AL + day 1 primaquine verses AL + day 3 primaquine or AL only arm was observed in mean gametocyte density. Mean (sd) haemoglobin level in AL + day 3 primaquine arm recovered from -0.42(1.2) g/dl on day 2 to 0.35 (1.5) g/dl on day 15 of follow up. This was not the case in AL only and AL + day 1 primaquine arms during the same follow-up period, although the difference was not statistically significant (p = 318). No serious adverse events reported in the study. Across arms, 23% (26/111) of participants reported a total of 31 mild adverse events and the difference was not statistically significant (p = 0.477).. Primaquine administration on the first day of AL is well tolerated and as safe as later administration. Whilst the World Health Organization currently recommends a lower dose of primaquine (0.25 mg/kg), the findings are supportive of early primaquine administration when combined with artemisinin-combination therapy. ClinicalTrials.gov Registration NCT01906788.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Carrier State; Child; Child, Preschool; Drug Therapy, Combination; Female; Hemoglobins; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Primaquine; Time Factors

Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance.. In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete.. Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50).. Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance.. UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Topics: Adolescent; Adult; Amodiaquine; Anthraquinones; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Plasmodium falciparum; Polymerase Chain Reaction; Quinolines; Treatment Outcome; Young Adult

In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia).. We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400.. Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported.. In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria.. Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Cluster Analysis; Humans; Malaria, Falciparum; Mass Drug Administration; Mosquito Control; Namibia; Plasmodium falciparum; Seroepidemiologic Studies

In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Microfilament Proteins; Mutation; Plasmodium falciparum; Protozoan Proteins; Quinolines; Senegal; Sequence Analysis, DNA; Treatment Failure

Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa.. Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence.. A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms.. Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://clinicaltrials.gov/show/NCT03241901.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Female; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Primaquine; Recurrence; Tanzania; Young Adult

Anti-malarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016.. This was a two-arm randomised controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated Plasmodium falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes.. A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labé. The majority of successfully analysed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13. All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analysed for pfmdr1.. This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Resistance; Female; Guinea; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Treatment Failure

Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern.. Male and non-pregnant females aged 1-65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4-5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively.. A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p = 0.010) and 13.4 ms (95% CI 5.3-21.5, p = 0.001), for QTcB and QTcF, respectively.. The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Electrocardiography; Female; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Single-Blind Method; Tanzania; Young Adult

The purpose of this study was to update efficacy data of Artesunate-Amodiaquine (AS+AQ) and Artemether-Lumefantrine (AL) used as first-line malaria treatment in Côte d'Ivoire since 2005. This was an open-label, randomized trial conducted in patients older than 6 months with uncomplicated P. falciparum malaria at six sentinel sites. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used with primary outcomes as ACPR corrected by PCR at day 42. Secondary endpoints were parasite and fever clearance times and safety. From January to July 2016, 712 patients were included in the trial. 353 and 359 patients were randomly assigned respectively to the AS+AQ and AL arm. Day 42 PCR-adjusted ACPR in the per-protocol analysis was 99.4% and 98.8% in AS+AQ and AL arm respectively. Delayed parasite clearance was observed in six patients at Abidjan and Yamousssoukro sites. Both ACTs were well tolerated. Both ACTs remain efficacious for uncomplicated P. falciparum malaria treatment in Côte d'Ivoire. But regarding delayed parasite clearance observed in this study, a close monitoring and supervision for ACT resistance are essential for future malaria treatment and control strategies in Côte d'Ivoire.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Cote d'Ivoire; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria; Malaria, Falciparum; Treatment Outcome

Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) have been widely used for the treatment of uncomplicated Plasmodium falciparum malaria since 2005 in Gabon. Since 2011, a rebound of malaria morbidity has been observed in this country, while no survey evaluating ACT efficacy was performed. During the same period, parasite resistance against artemisinin has been reported in Asia. The aim of this study was to assess the efficacy and tolerability of these two drugs in two sentinel sites of Gabon 10 years after their implementation.. Children aged from 12 to 144 months with uncomplicated malaria were recruited at the Regional Hospital of Melen, Libreville and in the Urban Health Center of Franceville between March 2014 and September 2015. The therapeutic efficacy was evaluated according to the WHO 2008 protocol of 28-day follow-up and PCR-uncorrected/corrected treatment outcomes were assessed.. One hundred and eighty-five children (98 ASAQ and 89 AL) were followed up until day 28. The PCR-corrected ACPR was 98.9% for AS-AQ and 96.4% for AL. Late therapeutic failure rate was 3.6% and 1.1% for AL and AS-AQ, respectively (p = 0.2). Adverse events and serious adverse events were rarely observed with both treatments.. AS-AQ and AL are still efficacious and well-tolerated for the treatment of uncomplicated malaria in Gabonese children.

Topics: Amodiaquine; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Gabon; Humans; Infant; Malaria, Falciparum; Prospective Studies; Sentinel Surveillance; Treatment Outcome

Malaria remains a major public health problem, affecting mainly low-and middle-income countries. The management of this parasitic disease is challenged by ever increasing drug resistance. This study, investigated the therapeutic efficacy, tolerability and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), used as first-line drugs to treat uncomplicated malaria in Lambaréné, Gabon.. A non-randomized clinical trial was conducted between October 2017 and March 2018 to assess safety, clinical and parasitological efficacy of fixed-doses of AL and AS-AQ administered to treat uncomplicated Plasmodium falciparum malaria in children aged from 6 months to 12 years. After 50 children were treated with AL, another 50 children received ASAQ. The 2009 World Health Organization protocol for monitoring of the efficacy of anti‑malarial drugs was followed. Molecular markers msp1 and msp2 were used to differentiate recrudescence and reinfection. For the investigation of artemisinin resistant markers, gene mutations in Pfk13 were screened.. Per-protocol analysis on day 28 showed a PCR corrected cure rate of 97% (95% CI 86-100) and 95% (95% CI 84-99) for AL and AS-AQ, respectively. The most frequent adverse event in both groups was asthenia. No mutations in the kelch-13 gene associated with artemisinin resistance were identified. All participants had completed microscopic parasite clearance by day 3 post-treatment.. This study showed that AL and AS-AQ remain efficacious, well-tolerated, and are safe to treat uncomplicated malaria in children from Lambaréné. However, a regular monitoring of efficacy and a study of molecular markers of drug resistance to artemisinin in field isolates is essential. Trial registration ANZCTR, ACTRN12616001600437. Registered 18 November, http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12616001600437p&isBasic=True.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Monitoring; Female; Gabon; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Protozoan Proteins

In Uganda, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ) showed excellent treatment efficacy for uncomplicated malaria in prior trials. Because the frequency of resistance to artemisinins and piperaquine is increasing in Southeast Asia and the prevalence of Plasmodium falciparum polymorphisms associated with resistance has changed, we reassessed treatment efficacies at 3 sites in Uganda.. For this randomized, single-blinded clinical trial, children aged 6-59 months with uncomplicated falciparum malaria were assigned treatment with AL or DHA-PQ and followed for 42 days. Primary end points were risks of recurrent parasitemia, either unadjusted or adjusted to distinguish recrudescence from new infection. We assessed selection by study regimens of relevant P. falciparum genetic polymorphisms associated with drug resistance.. Of 599 patients enrolled, 578 completed follow-up. There were no early treatment failures. The risk of recurrent parasitemia was lower with DHA-PQ as compared to AL at all 3 sites at 42 days (26.0% vs 47.0%; P < .001). Recrudescent infections were uncommon in both the DHA-PQ and AL arms (1.1% and 2.2%, respectively; P = .25). Neither regimen selected for pfcrt or pfmdr1 polymorphisms associated with drug resistance.. AL and DHA-PQ remain effective for the treatment of malaria in Uganda. Neither regimen selected for genetic polymorphisms associated with drug resistance.. ISRCTN15793046.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Comparative Effectiveness Research; Drug Combinations; Drug Resistance; Female; Genotype; Humans; Infant; Malaria, Falciparum; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Quinolines; Recurrence; Single-Blind Method; Uganda

HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether-lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL.. A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul's Hospital in northern Zambia, involving 152 patients aged 15-65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population.. Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841-1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL.. AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx.

Topics: Adolescent; Adult; Aged; Alkynes; Antimalarials; Artemether, Lumefantrine Drug Combination; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Reverse Transcriptase Inhibitors; Young Adult; Zambia

To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk-benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa.. This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether-lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether-lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7.. Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A-) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A- genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether-lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up.. Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Cytochrome P-450 CYP2D6; Female; Gene Frequency; Genotype; Glucosephosphate Dehydrogenase; Humans; Lumefantrine; Malaria, Falciparum; Male; Mutation; Primaquine; South Africa; Treatment Outcome

Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA/PPQ) are the recommended first- and second-line treatments, respectively, for uncomplicated falciparum malaria in Somalia. The studies reported here were conducted to assess the efficacy of these artemisinin-based combinations and the mutations in Plasmodium falciparum K13-propeller (Pfk13) domain and amplification in Pfplasmepsin 2 (Pfpm2) gene in Somalia.. One-arm prospective studies were conducted to assess the clinical and parasitological responses to DHA/PPQ and AL at two sites in 2016 and 2017, respectively, using the standard WHO protocol. The patterns of molecular markers associated with artemisinin and PPQ resistance were investigated for the first time in Somalia.. A total of 339 patients were enrolled with 139 for AL and 200 for DHA/PPQ. With AL, no parasite recurrence was observed among patients treated at either site, corresponding to 100% clinical and parasitological responses. For DHA-PPQ, an adequate clinical and parasitological response rate > 97% was observed. All study patients on both treatments at both sites were parasite-free on day 3. Of the 138 samples with interpretable results for the polymorphism in Pfk13, only one (0.7%), from Bosaso, contained a non-synonymous mutation (R622I), which is not one of the known markers of artemisinin resistance. No Pfpm2 amplification was observed among the 135 samples with interpretable results.. AL and DHA/PPQ were highly effective in the treatment of uncomplicated falciparum malaria, and there was no evidence of resistance to artemisinin or PPQ. These two combinations are thus relevant in the chemotherapeutic strategy for malaria control in Somalia. Trial registration ACTRN12616001005448 (Jowhar DP study), ACTRN12616000553471 (Bosaso DP study), ACTRN12617001055392 (AL study in Bosaso and Jowhar).

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Female; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Quinolines; Somalia; Young Adult

We evaluated the therapeutic efficacy of artemether-lumefantrine (AL) fixed-dose combination to treat uncomplicated

Topics: Adolescent; Adult; Aged; Artemether, Lumefantrine Drug Combination; Brazil; Child; Child, Preschool; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium gallinaceum; Treatment Outcome; Young Adult

Pyronaridine-artesunate is a novel artemisinin-based combination therapy. The efficacy and safety of pyronaridine-artesunate were compared with artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children.. This phase III open-label randomized controlled non-inferiority trial was conducted in Western Kenya. Children aged 6 months to ≤ 12 years with a bodyweight > 5 kg and microscopically confirmed P. falciparum malaria were randomly assigned in a 1:1 ratio to orally receive pyronaridine-artesunate or artemether-lumefantrine, dosed according to bodyweight, for 3 days.. Of 197 participants, 101 received pyronaridine-artesunate and 96 received artemether-lumefantrine. The day-28 adequate clinical and parasitological response in the per-protocol population, PCR-corrected for reinfections, was 98.9% (93/94, 95% CI 94.2-99.8) for pyronaridine-artesunate and 96.4% (81/84, 95% CI 90.0-98.8) for artemether-lumefantrine. Pyronaridine-artesunate was found to be non-inferior to artemether-lumefantrine: the treatment difference was 2.5% (95% CI - 2.8 to 9.0). Adverse events occurred in 41.6% (42/101) and 34.4% (33/96) of patients in the pyronaridine-artesunate group and the artemether-lumefantrine group, respectively. No participants were found to have alanine or aspartate aminotransferase levels > 3 times the upper limit of normal.. Pyronaridine-artesunate was well tolerated, efficacious and non-inferior to artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria in Kenyan children. Results are in line with previous reports and inclusion of pyronaridine-artesunate in paediatric malaria treatment programmes should be considered. This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Child; Child, Preschool; Female; Humans; Infant; Kenya; Malaria, Falciparum; Male; Naphthyridines

Topics: Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Cluster Analysis; Drug Combinations; Female; Gene Expression; Genotype; Genotyping Techniques; Humans; Malaria, Falciparum; Malawi; Male; Merozoite Surface Protein 1; Merozoites; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Quinolines; Recurrence; Treatment Outcome

Artemisinin-based combinations differ in their impact on gametocyte prevalence and density. This study assessed female and male gametocyte dynamics after treating children with uncomplicated Plasmodium falciparum malaria with either pyronaridine-artesunate (PA) or artemether-lumefantrine (AL).. Kenyan children with uncomplicated Plasmodium falciparum malaria were included and randomly assigned to PA or AL treatment. Filter paper blood samples were collected as a source of RNA for quantitative reverse-transcription PCR (qRT-PCR) and nucleic acid sequence based amplification (QT-NASBA) to detect female gametocytes (targeting Pfs25 mRNA). Male gametocytes were detected by qRT-PCR (targeting PfMGET mRNA). Duration of gametocyte carriage, the female and male gametocyte response and the agreement between qRT-PCR and QT-NASBA were determined.. The mean duration of female gametocyte carriage was significantly longer for PA (4.9 days) than for AL (3.8 days) as estimated by QT-NASBA (P = 0.036), but this difference was less clear when determined by Pfs25 qRT-PCR (4.5 days for PA and 3.7 for AL, P = 0.166). qRT-PCR based female gametocyte prevalence decreased from 100% (75/75) at baseline to 6.06% (4/66) at day 14 in the AL group and from 97.7% (83/85) to 13.9% (11/79) in the PA group. Male gametocyte prevalence decreased from 41.3% (31/75) at baseline to 19.7% (13/66) at day 14 in the AL group and from 35.3% (30/85) to 22.8% (18/79) in the PA group. There was good agreement between Pfs25 qRT-PCR and QT-NASBA female gametocyte prevalence (0.85, 95% CI 0.82-0.87).. This study indicates that female gametocyte clearance may be slightly faster after AL compared to PA. Male gametocytes showed similar post-treatment clearance between study arms. Future studies should further address potential differences between the post-treatment transmission potential after PA compared to AL. Trial registration This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Child; Child, Preschool; Female; Humans; Infant; Kenya; Malaria, Falciparum; Male; Naphthyridines; Plasmodium falciparum; Reverse Transcriptase Polymerase Chain Reaction; Self-Sustained Sequence Replication

The spread of SP resistance may compromise the effectiveness of intermittent preventive treatment of malaria in pregnancy (MiP) with sulfadoxine-pyrimethamine (IPTp-SP) across Africa. However, there is no recommended alternative medicine for IPTp or alternative strategy for prevention of MiP. This poses problems for the prevention of MiP. This study investigated, whether screening with a rapid diagnostic test for malaria at routine antenatal clinic attendances and treatment of only those who are positive (intermittent screening and treatment) with artemether-lumefantrine is as effective and safe as IPTp-SP in pregnant women.. During antenatal clinic sessions at the General Hospital Calabar, Nigeria, held between October 2013 and November 2014, 459 pregnant women were randomized into either the current standard IPTp-SP or intermittent screening and treatment with artemether-lumefantrine (ISTp-AL). All women received a long-lasting insecticide-treated net at enrolment. Study women had a maximum of four scheduled visits following enrolment. Haemoglobin concentration and peripheral parasitaemia were assessed in the third trimester (36-40 weeks of gestation). Birth weight was documented at delivery or within a week for babies delivered at home.. In the third trimester, the overall prevalence of severe anaemia (Hb < 8 g/dl) and moderate (8-10.9 g/dl) anaemia was 0.8 and 27.7%, respectively, and was similar in both treatment groups (p = 0.204). The risk of third-trimester severe anaemia did not differ significantly between both treatment arms (risk difference - 1.75% [95% CI - 4.16 to 0.66]) although the sample was underpowered for this outcome due to several participants being unavailable to give a blood sample. The risk of third-trimester maternal parasitaemia was significantly lower in the ISTp-AL arm (RD - 3.96% [95% CI - 7.76 to - 0.16]). The risk of low birthweight was significantly lower in the ISTp-AL arm after controlling for maternal age, gravidity and baseline parasitaemia (risk difference - 1.53% [95% CI - 1.54 to - 1.15]). Women in the ISTp-AL arm complained of fever more frequently compared to women in the IPTp-SP arm (p = 0.022).. The trial results suggest that in an area of high malaria transmission with moderate sulfadoxine-pyrimethamine resistance, ISTp with artemether-lumefantrine may be an effective strategy for controlling malaria in pregnancy. Trial registration PACTR, PACTR201308000543272. Registered 29 April 2013, http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR201308000543272.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Chemoprevention; Drug Combinations; Female; Humans; Incidence; Malaria, Falciparum; Mass Screening; Nigeria; Parasitemia; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Prevalence; Pyrimethamine; Sulfadoxine; Young Adult

Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. In areas where resistance is established longer courses of artemisinin-based combination therapy have improved cure rates.. The standard 3-day course of artemether-lumefantrine (AL) was compared with an extended 5-day regimen for the treatment of uncomplicated falciparum malaria in Kayin state in South-East Myanmar, an area of emerging artemisinin resistance. Late parasite clearance dynamics were described by microscopy and quantitative ultra-sensitive PCR. Patients were followed up for 42 days.. Of 154 patients recruited (105 adults and 49 children < 14 years) 78 were randomized to 3 days and 76 to 5 days AL. Mutations in the P. falciparum kelch13 propeller gene (k13) were found in 46% (70/152) of infections, with F446I the most prevalent propeller mutation (29%; 20/70). Both regimens were well-tolerated. Parasite clearance profiles were biphasic with a slower submicroscopic phase which was similar in k13 wild-type and mutant infections. The cure rates were 100% (70/70) and 97% (68/70) in the 3- and 5-day arms respectively. Genotyping of the two recurrences was unsuccessful.. Despite a high prevalence of k13 mutations, the current first-line treatment, AL, was still highly effective in this area of South-East Myanmar. The extended 5 day regimen was very well tolerated, and would be an option to prolong the useful therapeutic life of AL. Trial registration NCT02020330. Registered 24 December 2013, https://clinicaltrials.gov/NCT02020330.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Mutation; Myanmar; Plasmodium falciparum; Protozoan Proteins; Time Factors; Treatment Outcome; Young Adult

Artemether-lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania. Recently, dihydroartemisinin-piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania. This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity.. This was an open-label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively. Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively. Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator. The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively.. Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively. In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji. With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p = 0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p = 0.021). The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites. Parasite clearance rate constant was similar in the two groups and at both sites (< 0.28/h); the slope half-life was < 3.0 h and all but only one patient cleared parasites by 72 h.. These findings confirm high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Tanzania. The high parasite clearance rate suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance. Trial registration This trial is registered at ClinicalTrials.gov under registration number NCT02590627.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Female; Humans; Infant; Malaria, Falciparum; Male; Quinolines; Tanzania

Artemether-lumefantrine (AL) and artesunate-amodiaquine are first-line treatment for uncomplicated malaria in many endemic countries, including Mali. Dihydroartemisinin-piperaquine (DHA-PQ) is also an alternative first-line artemisinin-based combination therapy, but only few data are available on DHA-PQ efficacy in sub-Saharan Africa. The main aim of this study was to compare clinical efficacy of DHA-PQ versus AL, using the World Health Organization (WHO) 42-day in vivo protocol.. The efficacy of three-dose regimens of DHA-PQ was compared to AL combination in a randomized, comparative open label trial using the WHO 42-day follow-up protocol from 2013 to 2015 in Doneguebougou and Torodo, Mali. The primary endpoint was to access the PCR-corrected Adequate Clinical and Parasitological Responses at day 28.. A total of 317 uncomplicated malaria patients were enrolled, with 159 in DHA-PQ arm and 158 in AL arm. The parasite positivity rate decreased from 68.4% (95% CI 60.5-75.5) on day 1 to 3.8% (95% CI 1.4-8.1) on day 2 for DHA-PQ and 79.8% (95% CI 72.3-85.7) on day 1 to 9.5% (95% CI 5.4-15.2) on day 2 for AL, (p = 0.04). There was a significant difference in the uncorrected ACPR between DHA-PQ and AL, both at 28-day and 42-day follow-up with 97.4% (95% CI 93.5-99.3) in DHA-PQ vs 84.5% (95% CI 77.8-89.8) in AL (p < 0.001) and 94.2% (95% CI 89.3-97.3) in DHA-PQ vs 73.4% (95% CI 65.7-80.2) in AL, respectively (p < 0.001). After molecular correction, there was no significant difference in ACPRc between DHA-PQ and AL, both at the 28-day and 42-day follow-up with 99.4% (95% CI 96.5-100) in DHA-PQ versus 98.1% (95% CI 94.5-99.6) in AL (p = 0.3) and 99.3% (95% CI 96.5-100) in DHA-PQ vs 97.4% (95% CI 93.5-99.3) in AL (p = 0.2). There was no significant difference between DHA-PQ and AL in QTc prolongation 12.1% vs 7%, respectively (p = 0.4).. The results showed that dihydroartemisinin-piperaquine and artemether-lumefantrine were clinically efficacious on Plasmodium falciparum parasites in Mali.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mali; Middle Aged; Plasmodium falciparum; Quinolines; Young Adult

In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy.. Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined.. AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Inhibitory Concentration 50; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Quinolines; Young Adult

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Burkina Faso; DNA, Protozoan; Double-Blind Method; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Primaquine; RNA, Protozoan; RNA, Ribosomal, 18S; Trophozoites

Primaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. It also clears mature P. falciparum (Pf) gametocytes, thereby reducing post-treatment transmission. Randomized PQ treatment in a treatment-to-reinfection cohort in Papua New Guinean children permitted the study of Pv and Pf gametocyte carriage after radical cure and to investigate the contribution of Pv relapses.. Children received radical cure with Chloroquine, Artemether-Lumefantrine plus either PQ or placebo. Blood samples were subsequently collected in 2-to 4-weekly intervals over 8 months. Gametocytes were detected by quantitative reverse transcription-PCR targeting pvs25 and pfs25.. PQ treatment reduced the incidence of Pv gametocytes by 73%, which was comparable to the effect of PQ on incidence of blood-stage infections. 92% of Pv and 79% of Pf gametocyte-positive infections were asymptomatic. Pv and to a lesser extent Pf gametocyte positivity and density were associated with high blood-stage parasite densities. Multivariate analysis revealed that the odds of gametocytes were significantly reduced in mixed-species infections compared to single-species infections for both species (ORPv = 0.39 [95% CI 0.25-0.62], ORPf = 0.33 [95% CI 0.18-0.60], p<0.001). No difference between the PQ and placebo treatment arms was observed in density of Pv gametocytes or in the proportion of Pv infections that carried gametocytes. First infections after blood-stage and placebo treatment, likely caused by a relapsing hypnozoite, were equally likely to carry gametocytes than first infections after PQ treatment, likely caused by an infective mosquito bite.. Pv relapses and new infections are associated with similar levels of gametocytaemia. Relapses thus contribute considerably to the Pv reservoir highlighting the importance of effective anti-hypnozoite treatment for efficient control of Pv.. ClinicalTrials.gov NCT02143934.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood; Child; Child, Preschool; Chloroquine; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Liver; Malaria, Falciparum; Malaria, Vivax; Male; Multivariate Analysis; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Primaquine; Recurrence; Regression Analysis; Risk Factors

Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria.. We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964.. Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2-4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference -6·1%, 95% CI -14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI -5·6 to 23·8).. The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended.. US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Quinolines; Young Adult

Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children.. This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days.. The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar.. The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients.. CTRI/2014/07/004764.

Topics: Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Heterocyclic Compounds, 1-Ring; Humans; India; Infant; Malaria, Falciparum; Male; Peroxides; Quinolines; Spiro Compounds; Survival Analysis; Tablets

Zambia is pushing for, and has made great strides towards, the elimination of malaria transmission in Southern Province. Reactive focal test and treat (RFTAT) using rapid diagnostic tests and artemether-lumefantrine (AL) has been key in making this progress. Reactive focal drug administration (RFDA) using dihydroartemisinin-piperaquine (DHAP), may be superior in accelerating clearance of the parasite reservoir in humans due to the provision of enhanced chemoprophylactic protection of at-risk populations against new infections. The primary aim of this study is to quantify the relative effectiveness of RFDA with DHAP against RFTAT with AL (standard of care) for reducing Plasmodium falciparum prevalence and incidence.. The study will be conducted in four districts in Southern Province, Zambia; an area of low malaria transmission and high coverage of vector control. A community randomized controlled trial of 16 health facility catchment areas will be used to evaluate the impact of sustained year-round routine RFDA for 2 years, relative to a control of year-round routine RFTAT. Reactive case detection will be triggered by a confirmed malaria case, e.g., by microscopy or rapid diagnostic test at any government health facility. Reactive responses will be performed by community health workers (CHW) within 7 days of the index case confirmation date. Responses will be performed out to a radius of 140 m from the index case household. A subset of responses will be followed longitudinally for 90 days to examine reinfection rates. Primary outcomes include a post-intervention survey of malaria seropositivity (n = 4800 children aged 1 month to under 5 years old) and a difference-in-differences analysis of malaria parasite incidence, as measured through routine passive case detection at health facilities enrolled in the study. The study is powered to detect approximately a 65% relative reduction in these outcomes between the intervention versus the control.. Strengths of this trial include a robust study design and an endline cross-sectional parasite survey as well as a longitudinal sample. Primary limitations include statistical power to detect only a 65% reduction in primary outcomes, and the potential for contamination to dilute the effects of the intervention.. ClinicalTrials.gov, ID: NCT02654912 . Registered on 12 November 2015.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Clinical Protocols; Community Health Services; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Incidence; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Prevalence; Quinolines; Research Design; Risk Factors; Time Factors; Treatment Outcome; Young Adult; Zambia

Quinine or alternative artemisinin-based combination treatment (ACT) is the recommended rescue treatment for uncomplicated malaria. However, patients are often re-treated with the same ACT though it is unclear whether this is the most suitable approach. We assessed the efficacy and safety of re-treating malaria patients with uncomplicated failures with the same ACT used for the primary episode, compared with other rescue treatments.. This was a bicentre, open-label, randomised, three-arm phase 3 trial done in Lisungi health centre in DR Congo, and Kazo health centre in Uganda in 2012-14. Children aged 12-60 months with recurrent malaria infection after treatment with the first-line ACT were randomly assigned to either re-treatment with the same first-line ACT, an alternative ACT, which were given for 3 days, or quinine-clindamycin (QnC), which was given for 5-7 days, following a 2:2:1 ratio. Randomisation was done by computer-generated randomisation list in a block design by country. The three treatment groups were assumed to have equivalent efficacy above 90%. Both the research team and parents or guardians were aware of treatment allocation. The primary outcome was the proportion of patients with an adequate clinical and parasitological response (ACPR) at day 28, in the per-protocol population. This trial was registered under the numbers NCT01374581 in ClinicalTrials.gov and PACTR201203000351114 in the Pan African Clinical Trials Registry.. From May 22, 2012, to Jan 31, 2014, 571 children were included in the trial. 240 children were randomly assigned to the re-treatment ACT group, 233 to the alternative ACT group, and 98 to the QnC group. 500 children were assessed for the primary outcome. 71 others were not included because they did not complete the follow-up or PCR genotyping result was not conclusive. The ACPR response was similar in the three groups: 91·4% (95% CI 87·5-95·2) for the re-treatment ACT, 91·3% (95% CI 87·4-95·1) for the alternative ACT, and 89·5% (95% CI 83·0-96·0) for QnC. The estimates for rates of malaria recrudescence in the three treatment groups were similar (log-rank test: χ. Re-treatment with the same ACT shows similar efficacy as recommended rescue treatments and could be considered for rescue treatment for Plasmodium falciparum malaria. However, the effect of this approach on the selection of resistant strains should be monitored to ensure that re-treatment with the same ACT does not contribute to P falciparum resistance.. Fonds Wetenschappelijk Onderzoek, Vlaamse Interuniversitaire Raad-Universitaire Ontwikkelings Samenwerking, European and Developing Countries Clinical Trials Partnership, and the Belgian Technical Cooperation-Programme d'Etudes et d'Expertises-in the Democratic Republic of Congo.

Topics: Amodiaquine; Anorexia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Clindamycin; Democratic Republic of the Congo; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Quinine; Treatment Outcome; Uganda

Short Message Service (SMS) reminders have been suggested as a potential intervention for improving adherence to medications and health facility attendance.. An open-label, randomized, controlled trial to test the efficacy of automated SMS reminders in improving adherence to artemether-lumefantrine (AL) and post-treatment attendance in comparison with standard care was conducted at four health facilities in western Kenya. Children below five years of age with uncomplicated malaria were randomized to intervention (SMS reminders) or control groups. Within each study group they were further randomized to three categories, which determined the timing of home visits to measure adherence to complete AL course and to individual AL doses. A sub-set of caregivers was advised to return to the facility on day 3 and all were advised to return after 28 days. The primary outcomes were adherence to medication and return on day 3. The primary analysis was by intention-to-treat.. Between 9 June, 2014 and 26 February, 2016, 1677 children were enrolled. Of 562 children visited at home on day 3, all AL doses were completed for 97.6% (282/289) of children in the control and 97.8% (267/273) in the intervention group (OR = 1.10; 95% CI = 0.37-3.33; p = 0.860). When correct timing in taking each dose was considered a criteria for adherence, 72.3% (209/289) were adherent in the control and 69.2% (189/273) in the intervention group (OR = 0.82; 95% CI = 0.56-1.19; p = 0.302). Sending SMS reminders significantly increased odds of children returning to the facility on day 3 (81.4 vs 74.0%; OR = 1.55; 95% CI = 1.15-2.08; p = 0.004) and on day 28 (63.4 vs 52.5%; OR = 1.58; 95% CI = 1.30-1.92; p < 0.001).. In this efficacy trial, SMS reminders increased post-treatment return to the health facility, but had no effect on AL adherence which was high in both control and intervention groups. Further effectiveness studies under the real world conditions are needed to determine the optimum role of SMS reminders. Trial registration ISRCTN39512726.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Caregivers; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Health Facilities; Humans; Infant; Kenya; Malaria, Falciparum; Male; Medication Adherence; Reminder Systems; Text Messaging

In treating malaria in Uganda, artemether-lumefantrine (AL) has been associated with a lower risk of recurrent parasitemia, compared with artesunate-amodiaquine (AS/AQ), but changing treatment practices may have altered parasite susceptibility.. We enrolled 602 children aged 6-59 months with uncomplicated falciparum malaria from 3 health centers in 2013-2014 and randomly assigned them to receive treatment with AS/AQ or AL. Primary outcomes were risks of recurrent parasitemia within 28 days, with or without adjustment to distinguish recrudescence from new infection. Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed.. Of enrolled patients, 594 (98.7%) completed the 28-day study. Risks of recurrent parasitemia were lower with AS/AQ at all 3 sites (overall, 28.6% vs 44.6%; P < .001). Recrudescences were uncommon, and all occurred after AL treatment (0% vs 2.5%; P = .006). Recovery of the hemoglobin level was greater with AS/AQ (1.73 vs 1.39 g/dL; P = .04). Both regimens were well tolerated; serious adverse events were uncommon (1.7% in the AS/AQ group and 1.0% in the AL group). AS/AQ selected for mutant pfcrt/pfmdr1 polymorphisms and AL for wild-type pfcrt/pfmdr1 polymorphisms associated with altered drug susceptibility.. AS/AQ treatment was followed by fewer recurrences than AL treatment, contrasting with older data. Each regimen selected for polymorphisms associated with decreased treatment response. Research should consider multiple or rotating regimens to maintain treatment efficacies.

Topics: Amodiaquine; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Uganda

Artemether/lumefantrine (Coartem(®)) has been used as a treatment for uncomplicated Plasmodium falciparum infection since 2004 in Benin. This open-label, non-randomized study evaluated efficacy of artemether-lumefantrine (AL) in treatment of uncomplicated falciparum malaria in children aged 6-59 months in two malaria transmission sites in northwest Benin.. A 42-day therapeutic efficacy study was conducted between August and November 2014, in accordance with 2009 WHO guidelines. One-hundred and twenty-three children, aged 6 months to 5 years, with uncomplicated falciparum malaria were recruited into the study. The primary endpoint was parasitological cure on day 28 and day 42 while the secondary endpoints included: parasite and fever clearance, improvement in haemoglobin levels. Outcomes were classified as early treatment failure (ETF), late clinical failure, late parasitological failure, and adequate clinical and parasitological response (ACPR).. Before PCR correction, ACPR rates were 87% (95 % CI 76.0-94.7) and 75.6%, respectively (95% CI 67.0-82.9) on day 28 and day 42. In each study site, ACPR rates were 78.3% in Djougou and 73% in Cobly on day 42. There was no ETF and after PCR correction ACPR was 100% in study population. All treatment failures were shown to be due to new infections. Fever was significantly cleared in 24 h and approximately 90% of parasites where cleared on day 1 and almost all parasites were cleared on day 2. Haemoglobin concentration showed a slight increase with parasitic clearance.. AL remains an efficacious drug for the treatment of uncomplicated falciparum malaria in Benin, although higher rates of re-infection remain a concern. Surveillance needs to be continued to detect future changes in parasite sensitivity to artemisinin-based combination therapy.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Benin; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male

Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa.. We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes.. The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups).. Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Topics: Adult; Africa; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Quinolines; Young Adult

Malaria causes significant morbidity in Malawi, with an estimated 5 million cases in 2014. Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first- and second-line treatments for uncomplicated malaria, respectively, but emerging resistance threatens their efficacy. In order to understand whether AL and ASAQ remain efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Malawi, a therapeutic efficacy trial was conducted.. During March-July 2014, febrile children aged 6-59 months with microscopy-confirmed uncomplicated P. falciparum malaria (1000-200,000 parasites/μL) were enrolled in a 28-day randomized in vivo efficacy trial at three sites: one each in northern (Karonga), central (Nkhotakota) and southern (Machinga) Malawi. The study was powered to estimate site-specific efficacy for AL and overall efficacy for ASAQ, with 3:1 randomization to AL or ASAQ. Blood was collected for malaria microscopy and molecular testing on days 0-3, 7, 14, 21, and 28. Recrudescence and reinfection were differentiated using polymerase chain reaction (PCR) genotyping of merozoite surface protein. The primary outcome was the PCR-corrected day 28 Kaplan-Meier cumulative success rate.. A total of 452 children were enrolled; 303/338 (89 %) and 98/114 (86 %) reached a study endpoint in AL and ASAQ arms, respectively. All treatment failures occurred after day 3. The day 28 uncorrected cumulative success rate was 97.1 % (95 % confidence interval [CI]: 93.9-100 %) for ASAQ and 76.8 % (95 % CI 72.1-81.5 %) for AL, with 82.5 % (95 % CI 75.4-89.7 %), 69 % (95 % CI 59.9-78.1 %), and 78.2 % (95 % CI 70.2-86.3 %) success in the northern, central, and southern regions, respectively. The day 28 PCR-corrected cumulative success rate was 99 % (95 % CI 97.2-100 %) in the ASAQ arm and 99.3 % (95 % CI 98.3-100 %) in the AL arm, with 98-100 % efficacy in each site.. As evidenced by the day 28 PCR-corrected cumulative success rates, both AL and ASAQ remain efficacious treatments for uncomplicated malaria in Malawi. The lower uncorrected efficacy in the AL arm compared to ASAQ may be explained by the shorter half-life of lumefantrine (3-6 days) compared to amodiaquine (9-18 days). The high reinfection rate suggests that there is a continued need to scale-up effective malaria prevention interventions.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malawi; Male; Plasmodium falciparum; Recurrence

This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.. Men and non-pregnant, non-lactating women aged ≥1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart™) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm.. Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [6.8, 95 % confidence interval (CI) 4.67-8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of ≥25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention.. The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania. Trial registration number NCT02090036.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Fluorenes; Genotyping Techniques; Glucosephosphate Dehydrogenase; Hemoglobins; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Primaquine; Single-Blind Method; Tanzania; Young Adult

The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.. A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged ≥1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection.. Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection.. The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania. Trial registration number NCT02090036.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Pregnancy; Primaquine; Single-Blind Method; Tanzania; Treatment Outcome; Young Adult

Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.. The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.. High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.. Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments. The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Genotype; Humans; Infant; Liberia; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Protozoan Proteins; Selection, Genetic

Between 2009 and 2012, malaria cases diagnosed in a Médecins sans Frontières programme have increased fivefold in Baraka, South Kivu, Democratic Republic of the Congo (DRC). The cause of this increase is not known. An in vivo drug efficacy trial was conducted to determine whether increased treatment failure rates may have contributed to the apparent increase in malaria diagnoses.. In an open-randomized non-inferiority trial, the efficacy of artesunate-amodiaquine (ASAQ) was compared to artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in 288 children aged 6-59 months. Included children had directly supervised treatment and were then followed for 42 days with weekly clinical and parasitological evaluations. The blood samples of children found to have recurring parasitaemia within 42 days were checked by PCR to confirm whether or not this was due to reinfection or recrudescence (i.e. treatment failure).. Out of 873 children screened, 585 (67 %) were excluded and 288 children were randomized to either ASAQ or AL. At day 42 of follow up, the treatment efficacy of ASAQ was 78 % before and 95 % after PCR correction for re-infections. In the AL-arm, treatment efficacy was 84 % before and 99.0 % after PCR correction. Treatment efficacy after PCR correction was within the margin of non-inferiority as set for this study. Fewer children in the AL arm reported adverse reactions.. ASAQ is still effective as a treatment for uncomplicated malaria in Baraka, South Kivu, DRC. In this region, AL may have higher efficacy but additional trials are required to draw this conclusion with confidence. The high re-infection rate in South-Kivu indicates intense malaria transmission. Trial registration NCT02741024.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Democratic Republic of the Congo; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Treatment Outcome

Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans.. In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates.. The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07-1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment.. We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes.. NCT0160325.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Culicidae; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Insecticides; Ivermectin; Malaria, Falciparum; Male

Artemether-lumefantrine and artesunate-amodiaquine are first-line treatment for uncomplicated malaria in Cameroon. No study has yet compared the efficacy of these drugs following the WHO recommended 42-day follow-up period. The goal of this study was to compare the clinical efficacy, tolerability and safety of artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL) and dihydroartemisinin piperaquine (DHAP) among children aged less than ten years in two malaria-endemic ecological regions of Cameroon.. A three-arm, randomized, controlled, non-inferiority trial was conducted among children of either gender aged six months (>5 kg) to ten years (n = 720) with acute uncomplicated Plasmodium falciparum infection. Parents/guardians of children provided consent prior to randomization to receive ASAQ, DHAP or AL in the ratio of 2:2:1, respectively. Treatment outcome was assessed based on standard WHO 2003 classification after 42 days of follow-up. The primary outcome was PCR-corrected day-42 cure rates. The non-inferiority, one-sided, lower limit asymptotic 97.5% confidence interval (CI) on the difference in PCR-corrected cure rates of ASAQ and DHAP when compared to AL was accepted if the lower limit of the CI was greater than -10%. Secondary outcomes were parasite and fever clearances and day 7 haemoglobin changes.. PCR-corrected PP cure rates of 96.7, 98.1 and 96.3, respectively, for AL, ASAQ and DHAP was observed. The lower bound of the one-sided 97.5% CI calculated around the difference between day-42 cure rate point estimates in AL and ASAQ groups, AL and DHAP groups were, -6% and -4% respectively. There were no statistical significant differences in parasite or fever clearance times between treatments, although fever clearance pattern was different between ASAQ and DHAP. No statistical significant differences were observed in the occurrence of adverse events among treatment groups.. ASAQ and DHAP are considered safe and tolerable and are not inferior to AL in the treatment of uncomplicated P. falciparum malaria in Cameroonian children.. NCT01845701.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cameroon; Child; Child, Preschool; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Quinolines; Treatment Outcome

This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa.. Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater.. A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window.. In this study, non-inferiority of AZCQ to AL was not demonstrated.. ClinicalTrials.gov NCT00677833 .

Topics: Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Azithromycin; Child; Child, Preschool; Chloroquine; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male

Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.. This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).. A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.. A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.. Clinicaltrials.gov NCT01619878.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Treatment Outcome

In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment.. For children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis.. Of 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P = 0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50-146) vs 116 (77-130) days, respectively (P = 0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P = 0.31).. The greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness.. Australian New Zealand Clinical Trials Registry ACTRN12610000913077 .

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Half-Life; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Treatment Outcome

Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded. Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking. The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile.. In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded. Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program. Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons.. This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children.. ClinicalTrials.gov: NCT01958905.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mali; Niger; Recurrence; Research Design; Severe Acute Malnutrition; Treatment Outcome

To compare the artesunate-amodiaquine and artemether-lumefantrine combinations in the treatment of acute uncomplicated falciparum malaria during pregnancy.. Between January and July, 2013, a double-blind randomized trial was undertaken of symptomatic pregnant women (second/third trimester) with malaria parasitemia who attended a center in Ile-Ife, Nigeria. Participants were assigned to receive artesunate-amodiaquine or artemether-lumefantrine (twice daily on days 1-3) according to a computer-generated randomization sequence. Participants and investigators were masked to group allocation. Clinical evaluations and malaria parasite counts were performed at baseline and on days 2, 3, 7, and 28. Mean interval to symptomatic relief, day-3 parasite clearance, day-28 cure rate, and adverse effects were assessed.. Of 75 women assigned to each group, 65 in the artesunate-amodiaquine group and 71 in the artemether-lumefantrine group completed the study. No significant differences between the artesunate-amodiaquine and artemether-lumefantrine groups were recorded for mean interval to symptomatic relief (2.2 ± 1.0 days vs 2.0 ± 0.8 days; P=0.090), day-3 parasite clearance (58/65 [89.2%] vs 66/71 [93.0%]; P=0.444), and day-28 cure rate (64/65 [98.5%] vs 67/71 [94.4%]; P=0.138). Adverse effects (body weakness and pruritus) were more common among women assigned to artesunate-amodiaquine (30/75 [40.0%]) than among those assigned to artemether-lumefantrine (2/75 [2.7%]; P<0.001).. Efficacies of the regimens are similar among pregnant women. However, adverse effects are more common with artesunate-amodiaquine. Pan-African Clinical Trial Registry: PACTR201310000484185.

Topics: Adolescent; Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Nigeria; Parasitemia; Pregnancy; Pregnancy Complications, Parasitic; Treatment Outcome; Young Adult

The development and spread of chloroquine-resistant Plasmodium falciparum threatens the health of millions of people and poses a major challenge to the control of malaria. Monitoring drug efficacy in 2-year intervals is an important tool for establishing rational anti-malarial drug policies. This study addresses the therapeutic efficacy of artemether-lumefantrine (AL) for the treatment of Plasmodium falciparum in southwestern Ethiopia.. A 28-day in vivo therapeutic efficacy study was conducted from September to December, 2011, in southwestern Ethiopia. Participants were selected for the study if they were older than 6 months, weighed more than 5 kg, symptomatic, and had microscopically confirmed, uncomplicated P. falciparum. All 93 eligible patients were treated with AL and followed for 28 days. For each patient, recurrence of parasitaemia, the clinical condition, and the presence of gametoytes were assessed on each visit during the follow-up period. PCR was conducted to differentiate re-infection from recrudescence.. Seventy-four (83.1 %) of the study subjects cleared fever by day 1, but five (5.6 %) had fever at day 2. All study subjects cleared fever by day 3. Seventy-nine (88.8 %) of the study subjects cleared the parasite by day 1, seven (7.9 %) were blood-smear positive by day 1, and three (3.4 %) were positive by day 2. In five patients (5.6 %), parasitaemia reappeared during the 28-day follow-up period. From these five, one (1.1 %) was a late clinical failure, and four (4.5 %) were a late parasitological failure. On the day of recurrent parasitaemia, the level of chloroquine/desethylchloroquine (CQ-DCQ) was above the minimum effective concentration (>100 ng/ml) in one patient. There were 84 (94.4 %) adequate clinical and parasitological responses. The 28-day, PCR-uncorrected (unadjusted by genotyping) cure rate was 84 (94.4 %), whereas the 28-day, PCR-corrected cure rate was 87 (97.8 %). Of the three re-infections, two (2.2 %) were due to P. falciparum and one (1.1 %) was due to P. vivax. From 89 study subjects, 12 (13.5 %) carried P. falciparum gametocytes at day 0, whereas the 28-day gametocyte carriage rate was 2 (2.2 %).. Years after the introduction of AL in Ethiopia, the finding of this study is that AL has been highly effective in the treatment of uncomplicated P. falciparum malaria and reducing gametocyte carriage in southwestern Ethiopia.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Microscopy; Middle Aged; Treatment Outcome; Young Adult

Several studies have reported high efficacy and safety of artemisinin-based combination therapy (ACT) mostly under strict supervision of drug intake and limited to children less than 5 years of age. Patients over 5 years of age are usually not involved in such studies. Thus, the findings do not fully reflect the reality in the field. This study aimed to assess the effectiveness and safety of ACT in routine treatment of uncomplicated malaria among patients of all age groups in Nanoro, Burkina Faso.. A randomized open label trial comparing artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) was carried out from September 2010 to October 2012 at two primary health centres (Nanoro and Nazoanga) of Nanoro health district. A total of 680 patients were randomized to receive either ASAQ or AL without any distinction by age. Drug intake was not supervised as pertains in routine practice in the field. Patients or their parents/guardians were advised on the time and mode of administration for the 3 days treatment unobserved at home. Follow-up visits were performed on days 3, 7, 14, 21, and 28 to evaluate clinical and parasitological resolution of their malaria episode as well as adverse events. PCR genotyping of merozoite surface proteins 1 and 2 (msp-1, msp-2) was used to differentiate recrudescence and new infection.. By day 28, the PCR corrected adequate clinical and parasitological response was 84.1 and 77.8 % respectively for ASAQ and AL. The cure rate was higher in older patients than in children under 5 years old. The risk of re-infection by day 28 was higher in AL treated patients compared with those receiving ASAQ (p < 0.00001). Both AL and ASAQ treatments were well tolerated.. This study shows a lowering of the efficacy when drug intake is not directly supervised. This is worrying as both rates are lower than the critical threshold of 90 % required by the WHO to recommend the use of an anti-malarial drug in a treatment policy.. NCT01232530.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Malaria, Falciparum; Male; Recurrence

Artemisinin-based combination treatments (ACTs) or intravenous artesunate are used in over 100 countries for uncomplicated or severe falciparum malaria. Although intravenous artesunate may cause delayed haemolytic anaemia, there is little evaluation of the temporal changes in haematocrit following ACTs.. Clinical and parasitological parameters were measured before and following treatment of uncomplicated falciparum malaria in children with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) over 6-weeks. Changes in haematocrit were characterized in individual patients based on a haematocrit <30 % or ≥30 % before and following treatment. Kinetics of the deficit in haematocrit from <30 % until attainment of ≥30 % were estimated by a non-compartment model.. In 248 of 1180 children eligible for evaluation, common temporal patterns were: no change or increase in haematocrit from ≥ 30 % [50 % of patients], haematocrit >30 % at presentation declining to <30 % within 2 weeks (early monophasic fall) [19 % of patients], and haematocrit <30 % at presentation increasing to ≥ 30 % [23 % of patients]. Haematocrit >30 % at presentation declining to <30 %, 3-5 weeks later (late monophasic fall) occurred in 7 children (3 %). Fall in haematocrit ≥5 units following treatment occurred in 57 children [23 %] between 14 and 28 days after treatment began. Baseline parasitaemia and proportion with > 100,000μL(-1) asexual forms were significantly higher in children with ≥5 units compared to <5 units fall in haematocrit 21 or 28 days after treatment began. Irrespective of pattern, declines in haematocrit deficit from <30 % were mono-exponential, with similar half-times for AA- and AL-treated children (1.32 d versus 1.14 d). Anaemia half-time correlated significantly positively with anaemia recovery time in the same patients (r = 0.55, P < 0.0001). Bland-Altman analysis of 9 or 10 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.19 or 0.63, respectively).. In uncomplicated falciparum malaria, increases or falls in haematocrit are common following ACTs. Falls in haematocrit ≥ 5 units are common and may or may not result in early or late anaemia. In children who recovered from acute falciparum malaria-associated anaemia following ACTs, decline in haematocrit deficit is mono-exponential.. Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 http://www.pactr.org .

Topics: Administration, Intravenous; Adolescent; Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Hematocrit; Humans; Infant; Malaria, Falciparum; Male; Prospective Studies; Treatment Outcome

The Republic of Congo adopted a new anti-malarial treatment policy in 2006, with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) as the first- and second-line anti-malarial drugs, respectively. Only three clinical studies had been conducted before the policy change. A randomized study on these two artemisinin-based combinations was conducted, and the effect that sickle cell trait may have on treatment outcomes was evaluated in children under 10 years old followed during 12 months in Brazzaville in 2010-2011.. A cohort of 330 children under 10 years of age living in a suburban area in the south of Brazzaville were passively followed for registration of malaria episodes. Uncomplicated Plasmodium falciparum episodes were randomly treated with co-formulated ASAQ (Coarsucam(®)) or AL (Coartem(®)). Patients were followed according to the 2009 World Health Organization protocol for the evaluation of anti-malarial drug efficacy. Plasmodium falciparum recrudescent isolates were compared to pre-treatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. PCR-uncorrected and PCR-corrected responses to treatment were determined using per protocol analysis. Haemoglobin type (AA, AS, SS) was determined by PCR.. Of 282 clinical malaria episodes registered during 1-year follow-up period, 262 children with uncomplicated malaria were treated with ASAQ (129 patients) or AL (133 patients). The PCR-corrected efficacy, expressed as the percentage of adequate clinical and parasitological response, was 97.0 % for ASAQ and 96.4 % for AL. Among ASAQ-treated patients, 112 (86.8 %) carried AA genotype and 17 (13.2 %) were AS carriers. The PCR-corrected efficacy was 96.4 % for AA-carriers and 100 % for AS-carriers treated with ASAQ [relative risk (RR) = 0.96; 95 % confidence interval, 0.93-1.00, p = 0.5]. Among 133 AL-treated children, 109 (82 %) carried AA, and 24 (18 %) AS genotypes. The PCR-corrected efficacy was 96.7 % among AA-carriers and 95.2 % among AS-carriers [RR = 1.01 (0.92-1.12), p = 0.6]. Nausea, jaundice, headache, dizziness, vomiting, pruritus, abdominal pain, and diarrhoea were registered as adverse events in both groups. ASAQ was associated with significantly more frequent adverse events (P < 0.05).. This first randomized study in Brazzaville confirmed the excellent efficacy of these co-formulated anti-malarial drugs in children. Sickle cell genotype did not influence the treatment efficacy of artemisinin-based combination therapy.

Topics: Amodiaquine; Anemia, Sickle Cell; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Congo; Drug Combinations; Ethanolamines; Female; Fluorenes; Genotype; Hemoglobins; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Recurrence; Suburban Population; Treatment Outcome

Artesunate + sulfadoxine-pyrimethamine (AS + SP) has been the first-line treatment and artemether-lumefantrine (AL) the second-line treatment for uncomplicated falciparum malaria in Yemen since 2005. This paper reports the results of studies conducted to monitor therapeutic efficacy of these two drugs in sentinel sites in Yemen.. Eight therapeutic efficacy studies were conducted in six sentinel sites during the period 2009-2013 in Yemen. Five studies were for the evaluation of AS + SP (total of 465 patients) and three studies (total of 268 patients) for the evaluation of AL. The studies were done according to standard WHO protocol 2009 with 28-day follow-up.. In the evaluation of AS + SP, the PCR-corrected cure rate was 98 % (95 % CI 92.2-99.5 %) in one site and 100 % in all of the other four sites. In the sites where AL was evaluated, the PCR-corrected cure rate was 100 % in all the sites. All patients were negative for asexual parasitaemia on day 3 in both the AS + SP and the AL groups. There was a higher rate of clearance of gametocytaemia in the AL-treated group when compared with the AS + SP groups from day 7 onwards.. AS + SP remains the effective drug for uncomplicated falciparum malaria in Yemen. AL is also highly effective and can be an appropriate alternative to AS + SP for the treatment of falciparum malaria. AL demonstrated a higher efficacy in clearing microscopic gametocytaemia than AS + SP.. Trial registration number ACTRN12610000696099.

Topics: Adolescent; Adult; Aged; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Prospective Studies; Pyrimethamine; Sulfadoxine; Treatment Outcome; Yemen; Young Adult

Primaquine is the only available drug that clears mature Plasmodium falciparum gametocytes in infected human hosts, thereby preventing transmission of malaria to mosquitoes. However, concerns about dose-dependent haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiencies have limited its use. We assessed the dose-response association of single-dose primaquine for gametocyte clearance and for safety in P falciparum malaria.. We undertook this randomised, double-blind, placebo-controlled trial with four parallel groups in Jinja district, eastern Uganda. We randomly allocated Ugandan children aged 1-10 years with uncomplicated falciparum malaria and normal G6PD enzyme function to receive artemether-lumefantrine, combined with either placebo or with 0.1 mg/kg, 0.4 mg/kg, or 0.75 mg/kg (WHO reference dose) primaquine base. Randomisation was done with computer-generated four-digit treatment assignment codes allocated to random dose groups in block sizes of 16. Study staff who provided care or assessed outcomes and the participants remained masked to the intervention group after assignment. The primary efficacy endpoint was the non-inferiority of the mean duration of gametocyte carriage in the test doses compared with the reference group of 0.75 mg primaquine per kg, with a non-inferiority margin of 2.5 days. The primary safety endpoint was the superiority of the arithmetic mean maximum decrease in haemoglobin concentration from enrolment to day 28 of follow-up in the primaquine treatment groups compared with placebo, with use of significance testing of pairwise comparisons with a cutoff of p=0.05. The trial is registered with ClinicalTrials.gov, number NCT01365598.. We randomly allocated 468 participants to receive artemether-lumefantrine combined with placebo (119 children) or with 0.1 mg/kg (116), 0.4 mg/kg (116), or 0.75 mg/kg (117) primaquine base. The mean duration of gametocyte carriage was 6.6 days (95% CI 5.3-7.8) in the 0.75 mg/kg reference group, 6.3 days (5.1-7.5) in the 0.4 mg/kg primaquine group (p=0.74), 8.0 days (6.6-9.4) in the 0.1 mg/kg primaquine group (p=0.14), and 12.4 days (9.9-15.0) in the placebo group (p<0.0001). No children showed evidence of treatment-related haemolysis, and the mean maximum decrease in haemoglobin concentration was not associated with the dose of primaquine received-it did not differ significantly compared with placebo (10.7 g/L, SD 11.1) in the 0.1 mg/kg (11.4 g/L, 9.4; p=0.61), 0.4 mg/kg (11.3 g/L, 10.0; p=0.67), or 0.75 mg/kg (12.7 g/L, 8.2; p=0.11) primaquine groups.. We conclude that 0.4 mg/kg primaquine has similar gametocytocidal efficacy to the reference 0.75 mg/kg primaquine dose, but a dose of 0.1 mg/kg was inconclusive for non-inferiority. Our findings call for the prioritisation of further trials into the efficacy and safety of doses of primaquine between 0.1 mg/kg and 0.4 mg/kg (including the dose of 0.25 mg/kg recently recommended by WHO), in view of the potential for widespread use of the drug to block malaria transmission.. Wellcome Trust and the Bill & Melinda Gates Foundation.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Parasite Load; Primaquine; ROC Curve; Treatment Outcome; Uganda

The efficacy of artemisinin-based combination therapy (ACT) has been established. The objective of the present study was to compare the efficacy and safety in the Central African Republic (CAR) of three commercially available artemisinin-based combinations, artemether + lumefantrine (AL), artesunate + sulphamethoxypyrazine-pyrimethamine (AS-SMP) and artesunate + amodiaquine (AS-AQ), with those of sulphadoxine-pyrimethamine + amodiaquine (SP-AQ), which was the first-line reference treatment in the country from 2004, until it was replaced by ACT in 2006 in accordance with changes in international recommendations based on resistance identified in other regions.. Children aged six to 59 months with uncomplicated Plasmodium falciparum malaria were recruited in Bangui, the capital of the CAR. The 251 patients selected were randomly assigned to receive AL (n = 60), AS-SMP (n = 58), AS-AQ (n = 68) or SP-AQ (n = 65) and were followed up for 28 days. Clinical outcome was classified according to the standard 2003 World Health Organization protocol.. At day 28, the cure rates in a per-protocol analysis were 92% (48/52) with AL, 93% (50/54) with AS-SMP, 93% (55/59) with AS-AQ and 100% (57/57) with SP-AQ, with no statistically significant difference between the four treatments. Defervescence was significantly faster with AS-AQ than with AL (p <0.035). Fatigue was reported significantly more frequently by patients receiving AQ than by those treated with AS-SMP or AL (p = 0.006). All the other adverse events reported were mild, and no significant difference was noted by treatment.. The three artemisinin-bsed combinations show similar, satisfactory results, comparable to that with SP-AQ. This evaluation is the first conducted in CAR since the official introduction of ACT. It should guide the National Malaria Control Programme in choosing the appropriate ACT for treatment of uncomplicated P. falciparum malaria in the future.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Central African Republic; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Prospective Studies

Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.. Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.. A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ≥38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.. Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.. Current Controlled Trials Identifier NCT00527800.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Kinetics; Longitudinal Studies; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Quinolines; Risk Factors; Uganda

This open-label, randomized study evaluated efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in treatment of uncomplicated falciparum malaria in children below five years of age, to build evidence on use of AL as first-line treatment and DP as second-line treatment in Kenya.. A total of 454 children aged six to 59 months with uncomplicated falciparum malaria were randomized (1:1) to receive AL dispersible or DP paediatric tablets and followed up for 42 days. Primary efficacy variable was corrected adequate clinical and parasitological response (ACPR) rate on day 28. Secondary variables included corrected (day 14, 28 and 42), uncorrected (day 3, 14, 28 and 42) cure rates, parasitological failure at days 3, 14 and 42. Acceptability and tolerability of both drugs were assessed by caregiver questionnaire.. On day 28, corrected ACPR rates for AL dispersible and DP paediatric were 97.8% (95% CI: 94.9-99.3) and 99.1% (95% CI: 96.8-99.9), respectively, in intention-to-treat population, with no significant treatment differences noted between AL dispersible and DP paediatric arms. Additionally, no significant differences were observed for PCR corrected cure rates on days 14 and ACPR on day 42 for AL dispersible (100%; 96.8%) and DP paediatric (100%; 98.7%). Similarly, for PCR uncorrected cure rates, no significant differences were seen on days 3, 14, 28, and 42 for AL dispersible (99.1%; 98.7%; 81.1%; 67.8%) and DP paediatric (100%; 100%; 87.7%; 70.5%). Parasite clearance was rapid, with approximately 90% clearance achieved in 40 hours in both treatment arms. Incidence of adverse events was related to underlying disease; malaria being reported in both treatment arms. One serious adverse event was noted in AL dispersible (0.42%) arm, not related to study drug. Adherence to treatment regimen was higher for children treated with AL dispersible (93.6%) compared to DP paediatric (85.6%). Acceptability of AL dispersible regimen was assessed as being significantly better than DP paediatric.. AL and DP were both efficacious and well tolerated, and had similar effects at day 42 on risk of recurrent malaria. No signs of Plasmodium falciparum tolerance to artemisinins were noted.. PACTR201111000316370.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Quinolines; Tablets

Artemisinin-based combination therapies (ACTs) are essential for the effective control of falciparum malaria in endemic countries. However, in most countries, such choice has been carried out without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ).. Between September 2008 and January 2010, 340 children were randomised to one of the two study arms and followed up for 42 days. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days.. The results showed a significantly higher unadjusted adequate clinical and parasitological response in the ASAQ (58.4%) than in the AL arm (46.1%) at day 28 but these trends were similar after correction with PCR data (ASAQ (89.7%) and AL (89.8%)). New infections started to appear after day 14, first in the AL and then in the ASAQ arm but at day 42 day of follow-up we observed no difference in the occurrence of recrudescent infection.. Despite a lower cure rate than those reported in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Kaplan-Meier Estimate; Malaria, Falciparum; Male; Therapeutic Equivalency

Artemisinin-based combination therapy (ACT) has become the standard of care for the treatment of uncomplicated Plasmodium falciparum malaria. Although several ACT regimens are approved, data guiding optimal choices of ACTs are limited. We compared short- and long-term outcomes in a cohort of young Ugandan children randomized to 2 leading ACTs.. Overall, 312 children were randomized to artemether-lumefantrine or dihydroartemisinin-piperaquine (DP) at the time of the first episode of uncomplicated malaria (median age, 10.5 months). The same treatment was given for all subsequent episodes of uncomplicated malaria and children were followed until they reached 5 years of age. The cohort included a subgroup that was human immunodeficiency virus (HIV) infected (n = 44) or HIV exposed (n = 175) and prescribed trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. Outcomes included time to recurrent malaria following individual treatments and the overall incidences of treatments for malaria, complicated malaria, and hospitalizations.. Among children not prescribed TMP-SMX prophylaxis, 4443 treatments for malaria were given over 790 person-years following randomization. Treatment with DP was associated with a lower hazard of recurrent malaria over the 84 days after treatment (hazard ratio, 0.66; 95% confidence interval [CI], .61-.70; P < .001). Children randomized to DP had a lower incidence of all treatments for malaria (incidence rate ratio [IRR], 0.85; 95% CI, .75-.96; P = .01), complicated malaria (IRR, 0.12; 95% CI, .04-.39; P < .001), and hospitalizations (IRR, 0.31; 95% CI, .13-.77; P = .01). Among children prescribed TMP-SMX prophylaxis, there were no significant differences in longitudinal outcomes.. Compared to artemether-lumefantrine, the use of DP to treat uncomplicated malaria delayed the time to recurrent malaria and reduced the incidences of treatments for malaria, complicated malaria, and hospitalizations.. NCT00527800.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cohort Studies; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; HIV Infections; Hospitalization; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Male; Quinolines; Recurrence; Time Factors; Treatment Outcome; Uganda

An open-label, randomized controlled trial was carried out in 2011-2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate, and artemether-lumefantrine. Six hundred eighty-four children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm. Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms (P=0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-piperaquine (P=0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (P=0.78). The last provided a longer posttreatment prophylactic effect than did the other two treatments. The day 7 plasma concentration of piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine. Thus, although cure rates were all satisfactory, they could be improved by increasing the dose. (This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no. ISRCTN20984426.).

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Democratic Republic of the Congo; Drug Combinations; Erythrocyte Count; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Quinolines; Treatment Outcome

The effects that artemether-lumefantrine (AL) has on gametocyte dynamics in the short-term have recently been described. However there is limited long-term longitudinal data on the effect of AL on gametocyte dynamics in asymptomatic children.. An epidemiological study was conducted in Kombewa, Western Kenya, in which 270 asymptomatic children aged between 12 and 47 months were enrolled. The subjects were randomized to receive either a course of AL or placebo at enrolment. Active follow-up was conducted for one year.. The gametocyte prevalence and density dynamics throughout the study period mirrored that of the asexual forms. The proportion of initially parasitaemic subjects becoming gametocytaemic was significantly lower in the AL arm for the first 12 weeks following randomization. The geometric mean gametocyte density was lower in the AL arm for 2 weeks following randomization. None of the variables of interest had a statistically significant effect on the duration of gametocytaemia. There is no effect seen in subjects who are not parasitaemic at the time of drug administration.. The treatment of asymptomatic parasitaemic subjects with AL results in a significant reduction in the proportion of subjects who become gametocytaemic for at least 12 weeks.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Carrier State; Child, Preschool; Cohort Studies; Drug Combinations; Epidemiologic Studies; Ethanolamines; Female; Fluorenes; Humans; Infant; Kenya; Longitudinal Studies; Malaria, Falciparum; Male; Parasitemia; Placebos; Plasmodium falciparum

Mozambique adopted artemisinin-based combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria in the year 2006, and since 2009 artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) have been proposed as alternative first-line treatments. A multicentre study was conducted in five sites across the country to assess the in vivo efficacy and tolerability of these two drugs.. Children aged six to 59 months with uncomplicated malaria were recruited between June 2011 and January 2012 in five sites across Mozambique (Montepuez, Dondo, Tete, Chokwe, and Manhiça), and treated with AL or ASAQ in a non-randomized study. Follow-up was organized following standard WHO recommendations for in vivo studies, and included daily visits during the three-day-long supervised treatment course, followed by weekly visits up to day 28. The study primary outcome was the day 28 PCR-corrected early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF), and adequate clinical and parasitological response (ACPR). PCR was performed centrally for all cases of recurrent parasitaemia from day 7 onwards to distinguish recrudescence from re-infection.. Four-hundred and thirty-nine (AL cohort; five sites) and 261 (ASAQ cohort, three sites) children were recruited to the study. Day 28 PCR-corrected efficacy for AL was 96.0% (335/339; 95% CI: 93.4-97.8), while for ASAQ it was 99.6% (232/233; 95% CI: 97.6-99.9). The majority of recurring parasitaemia cases throughout follow-up were shown to be re-infections by PCR. Both drugs were well tolerated, with the most frequent adverse event being vomiting (AL 4.5% [20/439]; ASAQ 9.6% [25/261]) and no significant events deemed related to the study drugs.. This study confirms that both AL and ASAQ remain highly efficacious and well tolerated for the treatment of uncomplicated malaria in Mozambican children. Studies such as these should be replicated regularly in the selected surveillance sentinel sites to continuously monitor the efficacy of these drugs and to rapidly detect any potential signs of declining efficacy to ACT, the mainstay of malaria treatment.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Kaplan-Meier Estimate; Malaria, Falciparum; Male; Mozambique; Treatment Outcome

The efficacy of 3-day regimens of artemether-lumefantrine and artesunate-amodiaquine were evaluated in 747 children < 5 years of age with uncomplicated malaria from six geographical areas of Nigeria. Fever clearance was significantly faster (P = 0.006) and the proportion of children with parasitemia 1 day after treatment began was significantly lower (P = 0.016) in artesunate-amodiaquine-compared with artemether-lumefantrine-treated children. Parasite clearance times were similar with both treatments. Overall efficacy was 96.3% (95% confidence interval [CI] 94.5-97.6%), and was similar for both regimens. Polymerase chain reaction-corrected parasitologic cure rates on Day 28 were 96.9% (95% CI 93.9-98.2%) and 98.3% (95% CI 96.1-99.3%) for artemether-lumefantrine and artesunate-amodiaquine, respectively. Gametocyte carriage post treatment was significantly lower than pretreatment (P < 0.0001). In anemic children, mean time to recovery from anemia was 10 days (95% CI 9.04-10.9) and was similar for both regimens. Both treatments were well tolerated and are safe and efficacious treatments of uncomplicated falciparum malaria in young Nigerian children.

Topics: Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Nigeria; Parasitemia; Prevalence; Treatment Outcome

Emergence of artemisinin resistance has raised concerns that the most potent anti-malarial drug may be under threat. Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are, respectively, the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. Constant monitoring by National Malaria Control Programme (NMCP) of drug efficacy is an important tool in establishing rational anti-malarial drug policies in Côte d'Ivoire.. In an open label, randomized controlled clinical trial, children and adults were randomized to receive AS-AQ or AL. Both drug regimens were given for three days, and follow-up was for 42 days. The primary endpoint was the 42-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 42 days of follow-up.. A total of 383 patients who were attending the Anonkoua-koute (Abidjan), Petit Paris (Korhogo) and Libreville (Man) hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive AS-AQ (188) and AL (195). The intention-to-treat analysis showed effectiveness rates of 94.7% and 96.4% for AS-AQ and AL, respectively on day 42. After adjustment for PCR, these rates were 96.8% and 99%, respectively. At day 42, in per-protocol analysis, Adequate clinical and parasitological response (ACPR) PCR uncorrected was 97.8% and 97.4% for AS-AQ and AL, respectively. The PCR adjusted ACPR was 100% for each combination and both regimens were well tolerated.. This study has shown the high efficacy of AS-AQ in patients of all ages with acute uncomplicated falciparum malaria and AS-AQ was non-inferior to AL. Continuous efficacy monitoring is recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cote d'Ivoire; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Treatment Outcome; Young Adult

In malaria-endemic countries, large proportions of infected individuals are asymptomatic, constituting a reservoir of parasites for infection of newly hatched mosquitoes. This study evaluated the impact of screening and treatment of asymptomatic carriers of Plasmodium falciparum.. Eighteen villages were randomized (1:1) to study arms and inhabitants participated in four community screening campaigns: three before the rainy season ~1 month apart, and the fourth after the rains at ~12 months. On day 1 of campaigns 1-3, asymptomatic carriers in the intervention arm were identified by rapid diagnostic test and treated with artemether-lumefantrine. Outcomes were symptomatic malaria with parasite density >5,000/μL per person-year in children < 5 years and change in haemoglobin between days 1 and 28 of campaign 1.. At 12 months, the number of symptomatic malaria episodes with a parasite density >5,000/μL per person-year in children < 5 years was not significantly different between arms (1.69 vs 1.60, p = 0.3482). Mean haemoglobin change in asymptomatic carriers during campaign 1 was greater in the intervention vs control arm (+0.53 g/dL vs -0.21 g/dL, p < 0.0001). ANCOVA demonstrated that mean asymptomatic carriage at the cluster level was lower in the intervention vs control arm at day 1 of campaigns 2 (5.0% vs 34.9%, p < 0.0001) and 3 (3.5% vs 31.5%, p < 0.0001), but showed only a small difference at day 1 of campaign 4 (34.6% vs 37.6%, p = 0.2982). Mean gametocyte carriage was lower in the intervention vs control arm at day 1 of campaigns 2 and 3 (0.7% vs 5.4%, p < 0.0001; 0.5% vs 5.8%, p < 0.0001), but was similar at day 1 of campaign 4 (4.9% vs 5.1%, p = 0.7208).. Systematic screening and treatment of asymptomatic carriers at the community level did not reduce clinical malaria incidence in the subsequent transmission season, indicating greater levels of parasite clearance are required to achieve a sustained impact in this setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Asymptomatic Diseases; Burkina Faso; Carrier State; Child; Child, Preschool; Clinical Laboratory Techniques; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Incidence; Infant; Malaria, Falciparum; Male; Mass Screening; Middle Aged; Pregnancy; Rural Population; Treatment Outcome; Young Adult

Artemisinin-based combination therapy (ACT) reduces the potential for malaria transmission, compared with non-ACTs. It is unclear whether this effect differs between ACTs.. A total of 298 children (age, 6 months to 10 years) with uncomplicated falciparum malaria were randomized to artemether-lumefantrine (AL; n = 153) or dihydroartemisinin-piperaquine (DP; n = 145) in Mbita, a community in western Kenya. Gametocyte carriage was determined by molecular methods on days 0, 1, 2, 3, 7, 14, 28, and 42 after treatment initiation. The gametocyte infectiousness to mosquitoes was determined by mosquito-feeding assays on day 7 after beginning therapy.. The cumulative risk of recurrent parasitemia on day 42 after initiation of treatment, unadjusted by polymerase chain reaction findings, was 20.7% (95% confidence interval [CI], 14.4-28.2) for AL, compared with 3.7% (95% CI, 1.2-8.5) for DP (P < .001). The mean duration of gametocyte carriage was 5.5 days (95% CI, 3.6-8.5) for AL and 15.3 days (95% CI, 9.7-24.2) for DP (P = .001). The proportion of mosquitoes that became infected after feeding on blood from AL-treated children was 1.88% (43 of 2293), compared with 3.50% (83 of 2371) for those that fed on blood from DP-treated children (P = .06); the oocyst burden among mosquitoes was lower among those that fed on blood from AL-treated children (P = .005) CONCLUSIONS: While DP was associated with a longer prophylactic time after treatment, gametocyte carriage and malaria transmission to mosquitoes was lower after AL treatment.. NCT00868465.

Topics: Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Culicidae; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Quinolines; Secondary Prevention; Time Factors; Treatment Outcome

To establish efficacy and safety of artesunate/lumefantrine fixed-dose combination (FDC) in comparison with artemether/lumefantrine FDC in treatment of uncomplicated Plasmodium falciparum malaria.. Confirmed cases of uncomplicated P. falciparum malaria were randomly assigned to receive artesunate (100 mg)/lumefantrine (480 mg) (ASLF FDC) or artemether (80 mg)/lumefantrine (480 mg) (AMLF FDC) tablets for 3 days. Patients were followed up on Day 7, 14, 21 and 28.. Of the 158 enrolled patients, 144 completed the study. Seventy-three patients (94.8%) from the ASLF group and 71 patients (94.7%) from the AMLF group showed parasite clearance within 48 h. The mean parasite clearance time was 25.40 ± 14.82 h in the ASLF group and 24 ± 13.32 h in the AMLF group (P = 0.542). All patients showed gametocyte clearance by Day 7 and remained gametocyte free till Day 28. Sixty-five patients (84.4%) from the ASLF group and 56 patients (74.7%) from the AMLF group were afebrile within 24 h. The mean fever clearance time was 17.38 ± 12.33 h in the ASLF group and 17.2 ± 12.01 h in the AMLF group (P = 0.929). There was one early treatment failure in the AMLF group as per WHO criteria. Improvement in haemoglobin and haematocrit was comparable in both the treatment groups. In the ASLF group, of the 25 (32.47%) patients anaemic at baseline, only seven (9.09%) reported anaemia on Day 28, while in the AMLF group, of the 14 (18.67%) patients anaemic at baseline, only four (5.33%) reported anaemia on Day 28. Both study medications were well tolerated.. Artesunate (100 mg)/lumefantrine (480 mg) fixed-dose combination could add one more option to currently available artemisinin combinations in treatment of uncomplicated P. falciparum malaria.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Humans; India; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Parasite Load; Plasmodium falciparum; Time Factors; Treatment Outcome; Young Adult

Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.. Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28.. Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis).. Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.. The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).

Topics: Adolescent; Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Young Adult

Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce.. An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured.. The day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017).. Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended.. The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Liberia; Malaria, Falciparum; Male; Treatment Outcome

Artemether-lumefantrine (AL) was adopted as first-line treatment for uncomplicated malaria in Kenya in 2006. Monitoring drug efficacy at regular intervals is essential to prevent unnecessary morbidity and mortality. The efficacy of AL and dihydroartemisinin-piperaquine (DP) were evaluated for the treatment of uncomplicated malaria in children aged six to 59 months in western Kenya.. From October 2010 to August 2011, children with fever or history of fever with uncomplicated Plasmodium falciparum mono-infection were enrolled in an in vivo efficacy trial in accordance with World Health Organization (WHO) guidelines. The children were randomized to treatment with a three-day course of AL or DP and efficacy outcomes were measured at 28 and 42 days after treatment initiation.. A total of 137 children were enrolled in each treatment arm. There were no early treatment failures and all children except one had cleared parasites by day 3. Polymerase chain reaction (PCR)-uncorrected adequate clinical and parasitological response rate (ACPR) was 61% in the AL arm and 83% in the DP arm at day 28 (p = 0.001). PCR-corrected ACPR at day 28 was 97% in the AL group and 99% in the DP group, and it was 96% in both arms at day 42.. AL and DP remain efficacious for the treatment of uncomplicated malaria among children in western Kenya. The longer half-life of piperaquine relative to lumefantrine may provide a prophylactic effect, accounting for the lower rate of re-infection in the first 28 days after treatment in the DP arm.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Male; Quinolines; Treatment Outcome

Parasite clearance time after artemisinin-based combination therapy (ACT) may be increasing in Asian and African settings. The association between parasite clearance following ACT and transmissibility is currently unknown.. We determined parasite clearance dynamics by duplex quantitative polymerase chain reaction (qPCR) in samples collected in the first 3 days after treatment of uncomplicated malaria with ACT. Gametocyte carriage was determined by Pfs25 quantitative nucleic acid sequence-based amplification assays; infectiousness to mosquitoes by membrane-feeding assays on day 7 after treatment.. Residual parasitemia was detected by qPCR in 31.8% (95% confidence interval [CI], 24.6-39.8) of the children on day 3 after initiation of treatment. Residual parasitemia was associated with a 2-fold longer duration of gametocyte carriage (P = .0007), a higher likelihood of infecting mosquitoes (relative risk, 1.95; 95% CI, 1.17-3.24; P = .015), and a higher parasite burden in mosquitoes (incidence rate ratio, 2.92; 95% CI, 1.61-5.31; P < .001). Children with residual parasitemia were also significantly more likely to experience microscopically detectable parasitemia during follow-up (relative risk, 11.25; 95% CI, 4.08-31.01; P < .001).. Residual submicroscopic parasitemia is common after ACT and is associated with a higher transmission potential. Residual parasitemia may also have consequences for individual patients because of its higher risk of recurrent parasitemia.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chi-Square Distribution; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Quinolines; Recurrence

Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains.. We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection.. NCT01374581 and PACTR201203000351114.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Clindamycin; Clinical Protocols; Democratic Republic of the Congo; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Incidence; Infant; Longitudinal Studies; Malaria, Falciparum; Male; Plasmodium falciparum; Quinine; Recurrence; Research Design; Retreatment; Time Factors; Treatment Outcome; Uganda

The development and spread of Plasmodium falciparum resistance to most commonly used antimalarials remain a major challenge in the control of malaria. Constant monitoring of drug efficacy is an important tool in establishing rational antimalarial drug policies.. A randomized comparative study was conducted at the Wesley Guild Hospital, Ilesa, Nigeria between February 2010 and September 2011 comparing the efficacy and safety of artemether-lumefantrine (Coartem) and fixed dose of artesunate plus amodiaquine (Larimal) in the treatment of uncomplicated P. falciparum malaria in children betweem 6 and 144 months of age. P. falciparum malaria parasitemia was assessed by microscopy and rapid diagnostic test. Drugs were administered according to age for three days under supervision. The primary efficacy endpoint was a day 28 PCR-corrected parasitological cure.. A total of 182 patients were enrolled in the two treatment groups, Coartem (n = 101) and Larimal (n = 81), and tested after 28 days. In the intention-to-treat population, Coartem (n = 101) and Larimal (n = 81) had a PCR-corrected cure rate of 98% and 100% respectively, while in the per-protocol population, Coartem (n = 89) and Larimal (n = 71) both had a PCR-corrected cure rate of 100% at day 28. Although parasite and fever clearance time was faster in the Larimal group, no significant difference was observed between the two drugs. No serious adverse effects  were reported.. Five years after being introduced in Nigeria, both Coartem and Larimal have been shown to be safe and highly effective in the treatment of uncomplicated P. falciparum malaria in children.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasite Load; Parasitemia; Polymerase Chain Reaction; Treatment Outcome

National Malaria Control Program (NMCP) of Bangladesh has introduced Artemisinin Based Combination (ACT), Coartem(R) (Artemether-Lumefantrine (AL), fixed dose combination, in the confirmed cases of uncomplicated P. falciparum malaria since 2004. Despite the reduction of mortality due to malaria, the development and spread of anti-malarial drug resistance wordwide posing a threat to the health services and will make it difficult to control malaria in Bangladesh in future. We need to have an alternative to Coartem which could be Artesunate-amodiaquine (AA) in a fixed dose combination (FDC), a cheaper altenative not yet evidenced to be effective and safe to our population. In this study we compared the efficacy and safety of Artemether + Lumefantrene (FDC, Coartem) with Artesunate +Amodiaquine tablets (100/270 mg FDC) for the treatment of uncomplicated P. falciparum malaria in three high risk multi-drug resistant malaria prevalent areas of Bangladesh. It was an open label randomized controlled trial conducted between December 2008 and November 2009 in 4 upazillas in patients over the age 12 to 60 years diagnosed as a case of uncomplicated P. falciparum malaria. The outcome of the cases were measured as clinical response, parasitological response, defervescence time and parasite clearance time. Drug safety was assessed by comparing the adverse events. A total of 252 cases were randomized to receive Artesunate + Amodiaquine (AA group, 147 cases) and Artemether + Lumefantrene (AL group, 106 cases), one lost to follow up at day 28 in AA group. The distribution of the cases was comparable by age, sex and study sites. Treatment success' response was observed 100% in the AL group and AA group had 99%, two failures with AA were late treatment failures and the difference was not statistically significant (p > .1). The parasitological sensitive (S) response was observed in 97% of cases in AL group and 95% in the AA group, and was not a statistically significant difference. There was no significant difference in deffervescence time and parasite clearance time between two groups of cases. No serious adverse events were observed. The frequencies of minor adverse events were insignificantly different between the two treatment groups. The two ACT regimen, AA and AL had no significant difference in efficacy and safety for treatment of Uncomplicated Malaria in Bangladesh. However, there were few more failures with AA regimen compared to AL regimen, which was not statisticall

Topics: Adolescent; Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bangladesh; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Treatment Outcome; Young Adult

Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; HIV Infections; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Multivariate Analysis; Parasitemia; Plasmodium falciparum; Post-Exposure Prophylaxis; Prevalence; Proportional Hazards Models; Quinolines; Risk Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Trophozoites; Uganda

A new dose regimen of artesunate and amodiaquine (NDRAA) based on age or body weight range was compared with standard dose regimen of artesunate and amodiaquine (SDRAA) calculated according to body weight and with fixed-dose artesunate-amodiaquine (FDAA) and artemether-lumefantrine (AL) in 304 children afflicted by malaria aged 15 years or younger. In initial comparison (n = 208), children on NDRAA received 1-3 times amodiaquine per kilogram of body weight and 1-1.5 times of artesunate per kilogram of body weight compared with those receiving SDRAA. Parasite but not fever clearance was significantly faster in children who received NDRAA (19.4 ± 8.4 hours vs. 24.6 ± 15.5 hours, P = 0.003). Polymerase chain reaction-uncorrected cure rates on days 28-42 were also significantly higher in children who received NDRAA (P < 0.02 in all cases). Therapeutic responses in children younger than 5 years (n = 96) treated with NDRAA, FDAA, and AL were similar. Changes in hematocrit values and reported adverse events after commencing therapy were similar in those who received NDRAA and SDRAA. All drug regimens were well tolerated. NDRAA based on age or body weight range is simple, is therapeutically superior to SDRAA calculated according to body weight, and is as efficacious as AL in children younger than 5 years.

Topics: Administration, Oral; Adolescent; Age Factors; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Combinations; Ethanolamines; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Polymerase Chain Reaction; Treatment Outcome

The therapeutic efficacy, changes in haematocrit and declines in parasitaemias were evaluated in 56 children with uncomplicated falciparum hyperparasitaemia after oral artesunate-amodiaquine or artemether-lumefantrine. All children recovered clinically within 2 days and without progression to severe malaria. Falls in haematocrit in the first 3 days after treatment began were similar and <5%. Declines in parasitaemias were monoexponential with both treatments with an estimated half-life of 1 h.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Hematocrit; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Plasmodium falciparum; Treatment Outcome

The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone-proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Atovaquone; Audiometry; Child; Colombia; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Evoked Potentials, Auditory, Brain Stem; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Plasmodium falciparum; Proguanil; Prospective Studies; Treatment Outcome; Young Adult

In India, chloroquine has been replaced by a combination of artesunate and sulfadoxine-pyrimethamine (AS-SP) for uncomplicated P. falciparum malaria. Other available combinations, artemether-lumefantrine (AM-LF) and artesunate-mefloquine (AS-MQ), not included in the national program, are widely used by private practitioners. Little is known about the therapeutic efficacy of these artemisinin combinations and the prevalence of molecular markers associated with antimalarial drug resistance. A total of 157 patients with P. falciparum monoinfection were recruited and randomized into three study groups (AS-SP, AM-LF, and AS-MQ). All patients were followed up for 42 days to study the clinical and parasitological responses according to the WHO protocol (2009). We assessed the polymorphism of the pfATPase6, pfcrt, pfdhfr, and pfdhps genes by the DNA-sequencing method. The PCR-corrected therapeutic efficacies of AS-SP, AM-LF, and AS-MQ were 90.6% (95% confidence interval [CI], 0.793 to 0.969), 95.9% (95% CI, 0.860 to 0.995), and 100% (95% CI, 0.927 to 1.00), respectively. No specific mutational pattern was observed in the pfATPase6 gene. All isolates had a K76T mutation in the pfcrt gene. In the pfdhfr-pfdhps genotype, quadruple mutation was frequent, and quintuple mutation was documented in 6.3% of P. falciparum isolates. The significant failure rate of AS-SP (9.5%), although within the limit (10%) for drug policy change, was due to SP failure because of prevailing mutations in pfdhfr, I(51)R(59)N(108), with pfdhps, G(437) and/or E(540). The efficacy of this ACT needs periodic monitoring. Artemether-lumefantrine and artesunate-mefloquine are effective alternatives to the artesunate-sulfadoxine-pyrimethamine combination.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Biomarkers; Calcium-Transporting ATPases; Child; Child, Preschool; Dihydropteroate Synthase; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; India; Malaria, Falciparum; Male; Mefloquine; Membrane Transport Proteins; Mutation; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Treatment Outcome

In order to implement community case management of malaria strategy in a rural area of intense transmission, of children using artemether-lumefantrine combination, we assessed the therapeutic efficacy of the medicine. We conducted an open label and uncontrolled clinical trial in an unique centre from September 2009 to December 2009 in children 6-59 months old who consulted at health facilities for uncomplicated malaria. The primary endpoint was clinical and parasitological cure rate at day 28 corrected by PCR. In total 106 children were enrolled. Parasite clearance at day 2 was 99.04% and the adequate clinical and parasitological response corrected by PCR at day 28 was 90.5%. Our results confirm that artemether-lumefantrine combination is still effective.

Topics: Age of Onset; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Rural Population; Treatment Outcome

This study was conducted to correlate blood concentrations of lumefantrine with treatment outcome for patients with Plasmodium falciparum malaria when the drug was given without specific instructions for administration with food. Patients with P. falciparum malaria in the highly endemic state of Orissa, India, were enrolled during 2008 and followed-up for 28 days after admistration of artemether-lumefantrine for three days according to a World Health Organization protocol. Drug concentration in whole blood was determined by using blood spots placed on filter paper on day 7. The technology is suitable for field studies. One hundred percent of the patients had an adequate clinical and parasitological response. These results confirm the efficacy of artemether-lumefantrine in persons from poor tribal communities when given without specific instructions regarding co-administration with food, despite high inter-individual variability in blood concentrations of lumefantrine.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; India; Infant; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Patient Compliance; Plasmodium falciparum; Treatment Outcome; Young Adult

We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2-25.3; 12-46) and 22.4 (20.3-24.5; 12-46) for the first and second microscopists, respectively (P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction-corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Laos; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Treatment Outcome; Young Adult

Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance.. Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data.. Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria.. Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy.. http://clinicaltrials.gov/ct2/show/NCT00495508.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Hemeproteins; Histocytochemistry; Humans; Infant, Newborn; Malaria, Falciparum; Placenta; Pregnancy; Pregnancy Complications, Infectious; Quinine; Treatment Outcome; Uganda; Young Adult

Dendritic cells (DCs) are highly specialized antigen-presenting cells that are crucial for initiation of immune responses. During naturally acquired malaria, DC number and function is reduced.. The timing of, parasitemia threshold of, and contribution of apoptosis to DC loss were prospectively evaluated in 10 men after experimental challenge with approximately 1800 Plasmodium falciparum-parasitized red blood cells (pRBCs) and after drug cure initiated at a parasite level of ≥ 1000 parasites/mL.. The nadir levels of total, myeloid, and plasmacytoid DCs occurred 8 days after infection. DC loss was partially attributable to apoptosis, which was first detected on day 5 (median parasite level, 238 parasites/mL) and maximal at day 7. Remaining DCs exhibited a reduced ability to uptake particulate antigen. DC numbers recovered approximately 60 hours after antimalarial drug administration. There was no loss of DC number or function before or after drug cure in 5 men inoculated with <180 pRBCs and treated on day 6, when their parasite level was approximately 200 parasites/mL.. Plasmodium causes DC loss in vivo, which is at least partially explained by apoptosis in response to blood-stage parasites. In primary infection, loss of DC number and function occurs early during the prepatent period and before or with onset of clinical symptoms. These findings may explain in part the inadequate development of immunity to blood-stage malaria infection.

Topics: Adult; Antimalarials; Apoptosis; Artemether, Lumefantrine Drug Combination; Artemisinins; Cytokines; Dendritic Cells; Drug Combinations; Ethanolamines; Fluorenes; Gene Expression Regulation; Humans; Lymphocyte Count; Malaria, Falciparum; Male; Monocytes; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Time Factors; Young Adult

In 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga.. Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed.. Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference -0.7%, one sided 95% CI -3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated.. Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces.. The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Democratic Republic of the Congo; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Genotype; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Secondary Prevention; Treatment Outcome

In Jimma Zone, Ethiopia, the first-line treatment of uncomplicated falciparum malaria has been changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (AL) in 2006. The objective of this study was to assess the effectiveness of AL in Jimma Zone two to three years after its broad introduction.. An open-label, single-arm, 42-day study of AL against falciparum malaria was conducted in four areas with moderate transmission in Jimma Zone between November 2008 and January 2009 and between August and December 2009. Patients (one-81 years) with uncomplicated Plasmodium falciparum mono-infection were consecutively enrolled. Follow-up visits were at day 2, 3, 7, 28 and 42 or any other day if symptoms reoccurred. Primary and secondary endpoints were PCR-corrected and uncorrected cure rates (molecular differentiation between recrudescence and re-infection) on days 28 and 42. Other secondary endpoints were gametocytaemia at day 7 and day 28, parasitaemia at day 2 and 3, and re-infection rates at day 28 and day 42.. Of 348 enrolled patients, 313 and 301 completed follow-up at day 28 and at day 42, respectively. No early treatment failure occurred. For per protocol analysis, PCR-uncorrected cure rates at day 28 and 42 were 99.1% (95% CI 98.0-100.0) and 91.1% (95% CI 87.9-94.3), respectively. PCR-corrected cure rates at day 28 and 42 were 99.4% (95% CI 98.5-100.0) and 94.7% (95% CI 92.2-97.2), respectively. PCR-corrected cure rate at day 42 for children ≤ 5 years was 90.6% (95% CI 82.4-98.7) only. Adverse events were in general mild to moderate. Incidence of new infections was 3.4% during 42 days, no new infections with Plasmodium vivax were observed. Microscopically detected gametocytaemia was reduced by 80% between day 0 and day 7.. In general, AL was effective and well tolerated in Jimma Zone, Ethiopia. However, the PCR-corrected recrudescence rate per-protocol at day 42 for children ≤ 5 years was 9.4%. Therefore, further development should be monitored on a regular basis as recommended by WHO.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Treatment Outcome; Young Adult

The use of community volunteers is expected to improve access to accurate diagnosis and timely treatment of malaria, using rapid diagnostic test (RDT) and artemisinin-based combination therapy (ACT). However, empirical data from the field are still limited. The aim of this study was to assess whether training village volunteers on the use of Paracheck-Pf® RDT and ACT (artemether-lumefantrine (AL)) for Plasmodium falciparum and presumptive treatment with chloroquine for Plasmodium vivax had an effect on the coverage of timely diagnosis and treatment and on mortality in malaria-endemic villages without health staff in Myanmar.. The study was designed as a cluster randomized controlled trial with a cross-sectional survey at baseline, a monthly visit for six months following the intervention (village volunteers trained and equipped with Paracheck-Pf®) and an endline survey at six months follow-up. Survey data were supplemented by the analysis of logbooks and field-based verbal autopsies. Villages with midwives (MW) in post were used as a third comparison group in the endline survey. Intention-to-treat analysis was used.. Of 38 villages selected, 21 were randomly assigned to the intervention (two villages failed to participate) and 17 to the comparison group. The two groups had comparable baseline statistics. The blood tests provided by volunteers every month declined over time from 279 tests to 41 but not in MW group in 18 villages (from 326 to 180). In the endline survey, among interviewed subjects (268 intervention, 287 in comparison, 313 in MW), the coverage of RDT was low in all groups (14.9%, SE 2.4% in intervention; 5.7%, SE 1.7% in comparison; 21.4%, SE 2.6% in MW) although the intervention (OR 3.2, 95% CI 1.5-6.7) and MW (OR 5.4, 95% CI 2.6-11.0) were more likely to receive a blood test. Mean (SE) of blood tests after onset of fever in days was delayed (intervention 3.6 (0.3); comparison 4.8 (1.3); MW 3.2 (0.4)). Malaria mortality rates per 100,000 populations in a year were not significantly different (intervention 130 SE 37; comparison 119 SE 34; MW 50 SE 18). None of the dead cases had consulted volunteers.. The results show that implementing volunteer programmes to improve the coverage of accurate and timely diagnosis with RDT and early treatment may be beneficial but the timeliness of detection and sustainability must be improved.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Chloroquine; Community Health Workers; Drug Combinations; Education, Medical; Ethanolamines; Female; Fluorenes; Health Services Research; Human Experimentation; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Myanmar; Professional Competence; Time Factors; Young Adult

to evaluate the safety and efficacy of a fixed combination of artemether-lumefantrine for likely use against failures of the artesunate-amodiaquine first line therapy.. the study was an open label single arm uncontrolled trial. we evaluated the safety and efficacy of standard artemether-lumefantrine therapy in 59 subjects with uncomplicated malaria caused by Plasmodium falciparum on the island of Sumba in eastern Indonesia. No treatment failures occurred up to day 35. One subject had recurrent parasitemia on day 42 that showed a genotype consistent with recrudescence. The efficacy of this therapy was thus estimated to be 98.3% (95% confidence interval=95%-100%). Descriptive analysis was done using the SPSS 12 computer software.. two hundred and thirteen P. falciparum patients met the inclusion criteria for in vivo efficacy study, 79 were given artemether-lumefantrine and 134 were treated under another protocol with artesunate-amodiaquine or sulfadoxine-pyrimethamine. Among 79 eligible subjects, 59 successfully completed the 42-day test. As expected, the mean PCT was longer than the mean FCT, i.e. 1.34 ± 0.67 (95% CI 1.21-1.47) and 1.05 ± 0.05 (95% CI 0.95-1.15) days, respectively. On day 3 of treatment, both fever and asexual stage of P. falciparum disappeared in all subjects. Observation until Day 35 showed that all of the 59 subjects treated with artemether-lumefantrine were cured.. the findings of this uncontrolled study suggest good safety and efficacy of artemether-lumefantrine for treatment of uncomplicated falciparum malaria on Sumba Island in the Lesser Sundas archipelago of eastern Indonesia.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Indonesia; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine; Recurrence; Sulfadoxine; Time Factors

Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.. This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.. Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition).. The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.. ClinicalTrials.gov: identifier NCT00541385.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Dosage Forms; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Naphthyridines; Parasite Load; Recurrence; Tablets; Treatment Outcome

This multicentre study was carried out in Cameroon, Ivory Coast and Senegal to evaluate the non-inferiority of the new paediatric formulation of artesunate/amodiaquine (AS+AQ)(Camoquin-Plus Paediatric®) in suspension form versus artemether/lumefantrine (AL)(Coartem®) in the management of African children with uncomplicated falciparum malaria.. It was an open randomized trial including children aged between 7 months and 7 years. The endpoints were Adequate Clinical and Parasitological Response (ACPR) at day 28, the clinical and biological tolerability. Statistical analyses were done in Intention To Treat (ITT) and in Per protocol (PP).. At the end of the study 481 patients were enrolled in the three countries (249 in the AS+AQ arm and 232 in the AL arm). ACRP in ITT after PCR correction did not show any statistical difference between the two groups with 97.6% for AS+AQ versus 94.8% for AL. In the PP analysis, the corrected ACRP were respectively 98.7% and 96.9% for the two regimens. The clinical tolerance was good without significant difference. Anaemia was significantly higher at D7 in the two groups compared to D0.. This study demonstrates the non-inferiority of AS+AQ versus AL, its efficacy and tolerance in the management of uncomplicated Plasmodium falciparum malaria in African children.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cameroon; Chemistry, Pharmaceutical; Child; Child, Preschool; Cote d'Ivoire; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Parasite Load; Senegal; Treatment Outcome

To evaluate the effects of antimalarial drugs on Plasmodium falciparum malaria-associated anemia, we use the area under the curve (AUC) of anemia levels after treatment as an approach to combine their duration and magnitude. The method involves numeric estimation, by trapezoidal rule, of AUC from a plot of deficit in hematocrit levels from 30% (the lower threshold of normal) versus time in anemic children. Using the method, we evaluated, in randomized trials, the effects of artesunate-mefloquine versus mefloquine alone and artemether-lumefantrine versus amodiaquine-artesunate on the time course of recovery from malaria-associated anemia in 109 children. Anemia resolution times were similar (10.9 ± 6.2 [standard deviation] versus 13.3 ± 8.9 days, P = 0.2), but mean AUC was significantly lower in artesunate-mefloquine- compared with mefloquine-treated children (35.5 ± 7.1 [standard error of mean] versus 49.8 ± 11.3 %·h, P = 0.02) indicating larger exposure to anemia in mefloquine-treated children. In artemether-lumefantrine- and amodiaquine-artesunate-treated children, both anemia resolution times (8.6 ± 5.3 [standard deviation] versus 8.6 ± 4.8 days, P = 0.98) and mean AUC (57.1 ± 12.9 [standard error of mean] versus 46.3 ± 8.7 %·h, P = 0.74) were similar. Estimation of AUC appears more robust than estimation of anemia resolution time in evaluating antimalarial drug effects and can be used in both observational studies and clinical trials assessing the effects of therapies on malaria-associated anemia.

Topics: Amodiaquine; Anemia; Antimalarials; Area Under Curve; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Hematocrit; Humans; Infant; Malaria; Malaria, Falciparum; Male; Mefloquine; Nigeria; Plasmodium falciparum

In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.. In a randomized open-label clinical trial, artemether-lumefantrine or chloroquine (50 mg/kg) were given as 6 divided doses over 3 days to children aged 6 months--15 years who had uncomplicated P. falciparum monoinfection. Drug concentrations were measured on day 7. P. falciparum multidrug resistance gene N86Y and pfcrt K76T alleles were identified.. The polymerase chain reaction-adjusted day 28 and 42 treatment efficacies were 162 (97%) of 168 and 155 (97%) of 161, respectively, for artemether-lumefantrine and 150 (95%) of 158 and 138 (94%) of 148, respectively, for chloroquine. When parasites with resistance-associated pfcrt 76T were treated, the day 28 efficacy of chloroquine was 87%. No severe drug-related adverse events were detected. Symptom resolution was similar with both treatments.. Both treatments achieved the World Health Organization-recommended efficacy for antimalarials that will be adopted as policy. High-dose chloroquine treatment regimes should be further evaluated with the aim of assessing chloroquine as a potential partner drug to artemisinin derivatives. Clinical trials registration. NCT00426439.

Topics: Adolescent; Amino Acid Substitution; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood Chemical Analysis; Child; Child, Preschool; Chloroquine; Chromatography, High Pressure Liquid; DNA, Protozoan; Drug Combinations; Ethanolamines; Female; Fluorenes; Guinea-Bissau; Humans; Infant; Malaria, Falciparum; Male; Membrane Transport Proteins; Mutation, Missense; Plasmodium falciparum; Point Mutation; Polymerase Chain Reaction; Protozoan Proteins; Treatment Outcome

To test the hypothesis that Artesunate-mefloquine paediatric (AS+MEF) is as effective as Artemether-lumefantrine (AL) in treating acute uncomplicated malaria in children.. In an open label, randomized controlled clinical trial, children aged 6-59 months were randomized to receive AS+MEF or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 28 days of follow-up.. One hundred and fifty-six patients with confirmed uncomplicated P. falciparum malaria were randomly assigned to receive AS+MEF (n = 77) or AL (n = 79). PCR-corrected day 28 cure rates for per protocol (PP) populations were 99% for AS+MEF and 97% (P = 1) for AL. For the intention to treat (ITT) population, cure rates were 96% for AS+MEF and 92% (P = 0.49) for AL. Both regimens were well tolerated.. AS+MEF is as effective as AL, and both combinations were efficacious and safe.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child, Preschool; Drug Combinations; Epidemiologic Methods; Ethanolamines; Female; Fever; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mefloquine; Plasmodium falciparum; Treatment Outcome

Malaria in Zambia remains a public health and developmental challenge, affecting mostly children under five and pregnant women. In 2002, the first-line treatment for uncomplicated malaria was changed to artemether-lumefantrine (AL) that has proved to be highly efficacious against multidrug resistant Plasmodium falciparum.. The study objective was to determine whether dihydroartemisinin-piperaquine (DHA/PQP) had similar efficacy, safety and tolerability as AL for the treatment of children with uncomplicated P. falciparum malaria in Ndola, Zambia.. Between 2005 and 2006, 304 children (6-59 months old) with uncomplicated P. falciparum were enrolled, randomized to AL (101) or DHA/PQP (203) and followed up for 42 days. Outcome of treatment was defined according to the standard WHO classification, i.e. early treatment failure (ETF), late clinical failure (LCF, late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR). Recurrent infections were genotyped to distinguish between recrudescence and new infection.. No ETF was observed. At day 28, PCR-uncorrected ACPR was 92% in the DHA/PQP and 74% in the AL arm (OR: 4.05; 95%CI: 1.89-8.74; p < 0.001). Most failure were new infections and PCR-corrected ACPR was similar in the two study arms (OR: 0.69; 95%CI: 0.22-2.26; p = 0.33). Similar results were observed for day 42, i.e. higher PCR-uncorrected ACPR for DHA/PQP, mainly due to the difference observed up to day 28, while the PCR-corrected ACPR was similar: DHA/PQP: 93% (179/192), AL: 93% (84/90), (OR: 0.92; 95%CI: 0.30-2.64; p = 0.85). Except for cough, more frequent in the DHA/PQP arm (p = 0.04), there were no differences between treatment arms in the occurrence of adverse events. Two serious adverse events were probably associated to AL treatment.. DHA/PQP was as efficacious, safe and well tolerated in treatment of uncomplicated malaria as AL, though in the latter group more new infections during the follow up were observed. DHA/PQP seems a potential candidate to be used as an alternative first-line or rescue treatment in Zambia.. ISRCTN16263443, at http://www.controlled-trials.com/isrctn.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Treatment Outcome; Zambia

Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home.. An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961.. A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p ≤ 0.046).. Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Parasitology; Polymerase Chain Reaction; Prospective Studies; Rural Population; Tanzania; Treatment Outcome

The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine co-formulated (AAcf) or co-packaged (AAcp) on malaria-associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post-initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children.

Topics: Amodiaquine; Anemia; Antimalarials; Area Under Curve; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Nigeria; Treatment Outcome

It has been proposed that artemisinin-based combination therapy (ACT) be subsidised in the private sector in order to improve affordability and access. This study in western Kenya aimed to evaluate the impact of providing subsidized artemether-lumefantrine (AL) through retail providers on the coverage of prompt, effective antimalarial treatment for febrile children aged 3-59 months.. We used a cluster-randomized, controlled design with nine control and nine intervention sublocations, equally distributed across three districts in western Kenya. Cross-sectional household surveys were conducted before and after the delivery of the intervention. The intervention comprised provision of subsidized packs of paediatric ACT to retail outlets, training of retail outlet staff, and community awareness activities. The primary outcome was defined as the proportion of children aged 3-59 months reporting fever in the past 2 weeks who started treatment with AL on the same day or following day of fever onset. Data were collected using structured questionnaires and analyzed based on cluster-level summaries, comparing control to intervention arms, while adjusting for other covariates. Data were collected on 2,749 children in the target age group at baseline and 2,662 at follow-up. 29% of children experienced fever within 2 weeks before the interview. At follow-up, the percentage of children receiving AL on the day of fever or the following day had risen by 14.6% points in the control arm (from 5.3% [standard deviation (SD): 3.2%] to 19.9% [SD: 10.0%]) and 40.2% points in the intervention arm (from 4.7% [SD: 3.4%] to 44.9% [SD: 11.7%]). The percentage of children receiving AL was significantly greater in the intervention arm at follow-up, with a difference between the arms of 25.0% points (95% confidence interval [CI]: 14.1%, 35.9%; unadjusted p = 0.0002, adjusted p = 0.0001). No significant differences were observed between arms in the proportion of caregivers who sought treatment for their child's fever by source, or in the child's adherence to AL.. Subsidizing ACT in the retail sector can significantly increase ACT coverage for reported fevers in rural areas. Further research is needed on the impact and cost-effectiveness of such subsidy programmes at a national scale.. Current Controlled Trials ISRCTN59275137 and Kenya Pharmacy and Poisons Board Ethical Committee for Clinical Trials PPB/ECCT/08/07.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cost-Benefit Analysis; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Female; Fluorenes; Health Services Accessibility; Humans; Infant; Kenya; Malaria, Falciparum; Male; Plasmodium falciparum; Private Sector; Rural Health Services; Rural Population; Treatment Outcome

The choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.. A multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.. Of 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p=0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with Plasmodium falciparum. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.. Dihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cameroon; Child; Child, Preschool; Cote d'Ivoire; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Quinolines; Senegal; Treatment Outcome; Young Adult

In vivo efficacy assessments of the first-line treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. In Ethiopia, artemether-lumefantrine (AL) has been the first-line treatment for uncomplicated P. falciparum malaria since 2004.. Between October and November 2009, we conducted a 42-day, single arm, open label study of AL for P. falciparum in individuals >6 months of age at two sites in Oromia State, Ethiopia. Eligible patients who had documented P. falciparum mono-infection were enrolled and followed according to the standard 2009 World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response on days 28 and 42, respectively.. Of 4426 patients tested, 120 with confirmed falciparum malaria were enrolled and treated with AL. Follow-up was completed for 112 patients at day 28 and 104 patients at day 42. There was one late parasitological failure, which was classified as undetermined after genotyping. Uncorrected cure rates at both day 28 and 42 for the per protocol analysis were 99.1% (95% CI 95.1-100.0); corrected cure rates at both day 28 and 42 were 100.0%. Uncorrected cure rates at day 28 and 42 for the intention to treat analysis were 93.3% (95% CI 87.2-97.1) and 86.6% (95% CI 79.1-92.1), respectively, while the corrected cure rates at day 28 and 42 were 94.1% (95% CI 88.2-97.6) and 87.3% (95% CI 79.9-92.7), respectively. Using survival analysis, the unadjusted cure rate was 99.1% and 100.0% adjusted by genotyping for day 28 and 42, respectively. Eight P. falciparum patients (6.7%) presented with Plasmodium vivax infection during follow-up and were excluded from the per protocol analysis. Only one patient had persistent parasitaemia at day 3. No serious adverse events were reported, with cough and nausea/vomiting being the most common adverse events.. AL remains a highly effective and well-tolerated treatment for uncomplicated falciparum malaria in the study setting after several years of universal access to AL. A high rate of parasitaemia with P. vivax possibly from relapse or new infection was observed.. NCT01052584.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Survival Analysis; Treatment Outcome; Young Adult

The use of artemisinin-based combination therapy (ACT) is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT--artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--in subsequent episodes of Plasmodium falciparum malaria.. A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥ 12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR) after polymerase chain reaction (PCR) correction on day 28 for the first episode.. A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182) and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182), PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03). No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during treatment with no clinical consequence.. Study results confirmed the satisfactory efficacy and safety profile of ASAQ and AL. Moreover, in patients who were treated at least twice, repeated administration of ASAQ or AL did not identify any major safety issues.. ClinicalTrials.gov identifier NCT00540410.

Topics: Adolescent; Adult; Aged; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Recurrence; Senegal; Treatment Outcome; Young Adult

Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.. Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.. This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.. ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750

Topics: Adult; Africa South of the Sahara; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.. On the Kenyan coast we studied the treatment responses in 474 children 6-59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995).. The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (odds ratio, 5.4, 95%CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7-9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005-2006 and 2007-2008 (OR body temperature >37.5°C, 2.8, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.. The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.. Controlled-Trials.com ISRCTN88705995.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Male; Plasmodium falciparum; Quinolines; Survival Rate

It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.. In a 2×2 factorial trial, 612 rural Tanzanian children aged 6-60 months in an area with intense malaria transmission and with height-for-age z-score≤-1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥ 8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191-296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93-1.18 and 1.10, 0.97-1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.. We found no evidence from this trial that zinc supplementation protected against malaria.. ClinicalTrials.gov NCT00623857

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Dietary Supplements; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Incidence; Infant; Iron; Iron Deficiencies; Malaria; Malaria, Falciparum; Male; Malnutrition; Micronutrients; Prevalence; Regression Analysis; Tanzania; Zinc

Current malaria control strategies recommend (i) early case detection using rapid diagnostic tests (RDT) and treatment with artemisinin combination therapy (ACT), (ii) pre-referral rectal artesunate, (iii) intermittent preventive treatment and (iv) impregnated bed nets. However, these individual malaria control interventions provide only partial protection in most epidemiological situations. Therefore, there is a need to investigate the potential benefits of integrating several malaria interventions to reduce malaria prevalence and morbidity.. A randomized controlled trial was carried out to assess the impact of combining seasonal intermittent preventive treatment in children (IPTc) with home-based management of malaria (HMM) by community health workers (CHWs) in Senegal. Eight CHWs in eight villages covered by the Bonconto health post, (South Eastern part of Senegal) were trained to diagnose malaria using RDT, provide prompt treatment with artemether-lumefantrine for uncomplicated malaria cases and pre-referral rectal artesunate for complicated malaria occurring in children under 10 years. Four CHWs were randomized to also administer monthly IPTc as single dose of sulphadoxine-pyrimethamine (SP) plus three doses of amodiaquine (AQ) in the malaria transmission season, October and November 2010. Primary end point was incidence of single episode of malaria attacks over 8 weeks of follow up. Secondary end points included prevalence of malaria parasitaemia, and prevalence of anaemia at the end of the transmission season. Primary analysis was by intention to treat. The study protocol was approved by the Senegalese National Ethical Committee (approval 0027/MSP/DS/CNRS, 18/03/2010).. A total of 1,000 children were enrolled. The incidence of malaria episodes was 7.1/100 child months at risk [95% CI (3.7-13.7)] in communities with IPTc + HMM compared to 35.6/100 child months at risk [95% CI (26.7-47.4)] in communities with only HMM (aOR = 0.20; 95% CI 0.09-0.41; p = 0.04). At the end of the transmission season, malaria parasitaemia prevalence was lower in communities with IPTc + HMM (2.05% versus 4.6% p = 0.03). Adjusted for age groups, sex, Plasmodium falciparum carriage and prevalence of malnutrition, IPTc + HMM showed a significant protective effect against anaemia (aOR = 0.59; 95% CI 0.42-0.82; p = 0.02).. Combining IPTc and HMM can provide significant additional benefit in preventing clinical episodes of malaria as well as anaemia among children in Senegal.

Topics: Amodiaquine; Anemia; Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Community Health Workers; Disease Management; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Health Promotion; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Prevalence; Preventive Health Services; Pyrimethamine; Rural Population; Seasons; Senegal; Sulfadoxine

Artemisinin-based combination therapy, including artemether-lumefantrine (AL), is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. The objectives of the current analysis were to compare the efficacy and safety of AL across different body weight ranges in African children, and to examine the age and body weight relationship in this population.. Efficacy, safety and pharmacokinetic data from a randomized, investigator-blinded, multicentre trial of AL for treatment of acute uncomplicated P. falciparum malaria in infants and children in Africa were analysed according to body weight group.. The trial included 899 patients (intent-to-treat population 886). The modified intent-to-treat (ITT) population (n = 812) comprised 143 children 5 to < 10 kg, 334 children 10 to < 15 kg, 277 children 15 to < 25 kg, and 58 children 25 to < 35 kg. The 28-day PCR cure rate, the primary endpoint, was comparable across all four body weight groups (97.2%, 98.9%, 97.8% and 98.3%, respectively). There were no clinically relevant differences in safety or tolerability between body weight groups. In the three AL body weight dosing groups (5 to < 15 kg, 15 to < 25 kg and 25 to < 35 kg), 80% of patients were aged 10-50 months, 46-100 months and 90-147 months, respectively.. Efficacy of AL in uncomplicated falciparum malaria is similar across body weight dosing groups as currently recommended in the label with no clinically relevant differences in safety or tolerability. AL dosing based on body weight remains advisable.

Topics: Age Factors; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Time Factors; Treatment Outcome

In Uganda, parasite-based diagnosis is recommended for every patient suspected to have malaria before prescribing anti-malarials. However, the majority of patients are still treated presumptively especially in low-level health units. The feasibility of implementing parasite-based diagnosis for uncomplicated malaria in rural health centres (HCs) was investigated with a view to recommending measures for scaling up the policy.. Thirty HCs were randomized to implement parasite-based diagnosis based on rapid diagnostic tests [RDTs] (n = 10), blood microscopy (n = 10) and presumptive diagnosis (control arm) (n = 10). Feasibility was assessed by comparing the proportion of patients who received parasite-based diagnosis; with a positive malaria parasite-based diagnosis who received artemether-lumefantrine (AL); with a negative malaria parasite-based diagnosis who received AL; and patient waiting time. Clinicaltrials.gov: NCT00565071.. 102, 087 outpatients were enrolled. Patients were more likely to be tested in the RDT 44, 565 (96.6%) than in microscopy arm 19, 545 (60.9%) [RR: 1.59]. RDTs reduced patient waiting time compared to microscopy and were more convenient to health workers and patients. Majority 23, 804 (99.7%) in presumptive arm were prescribed AL. All (100%) of patients who tested positive for malaria in RDT and microscopy arms were prescribed anti-malarials. Parasitological-based diagnosis significantly reduced AL prescription in RDT arm [RR: 0.62] and microscopy arm [RR: 0.72] compared to presumptive treatment. Among patients not tested in the two intervention arms, 12, 044 (96.1%) in microscopy and 965 (61.6%) in RDT arm were treated with AL [RR: 1.56]. Overall 10, 558 (29.4%) with negative results [5, 110 (23.4%) in RDT and 5, 448 (39.0%) in microscopy arms] were prescribed AL.. It was more feasible to implement parasite-based diagnosis for malaria using RDT than with microscopy. A high proportion of patients with negative malaria results are still prescribed anti-malarials. There is need to increase access to parasite-based diagnosis where microscopy is used. In order to fully harness the benefits of parasitological confirmation of malaria, it is necessary to reduce the prescription of anti-malarials in negative patients.

Topics: Adolescent; Adult; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Delivery of Health Care; Diagnostic Tests, Routine; Drug Combinations; Ethanolamines; Feasibility Studies; Female; Fever; Fluorenes; Health Personnel; Humans; Inappropriate Prescribing; Infant; Malaria, Falciparum; Male; Microscopy; Plasmodium falciparum; Practice Patterns, Physicians'; Rural Health Services; Time Factors; Uganda; Young Adult

This study aimed to explore Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment with artemisinin-based combination therapy in children with clinical malaria in a high transmission area in Africa.. A total of 50 children aged 1-10 years with acute uncomplicated P. falciparum malaria in Bagamoyo District, Tanzania, were enrolled. Participants were hospitalized and received supervised standard treatment with artemether-lumefantrine according to body weight in six doses over 3 days. Blood samples were collected 11 times, i.e. at time of diagnosis (-2 h) and 0, 2, 4, 8, 16, 24, 36, 48, 60 and 72 h after initiation of treatment. Parasite population dynamics were assessed using nested polymerase chain reaction (PCR)-genotyping of merozoite surface protein (msp) 1 and 2.. PCR-analyses from nine sequential blood samples collected after initiation of treatment identified 20 and 21 additional genotypes in 15/50 (30%) and 14/50 (28%) children with msp1 and msp2, respectively, non-detectable in the pre-treatment samples (-2 and 0 h combined). Some 15/20 (75%) and 14/21 (67%) of these genotypes were identified within 24 h, whereas 17/20 (85%) and 19/21 (90%) within 48 h for msp1 and msp2, respectively. The genotype profile was diverse, and varied considerably over time both within and between patients, molecular markers and their respective families.. PCR analyses from multiple blood samples collected during the early treatment phase revealed a complex picture of parasite sub-populations. This underlines the importance of interpreting PCR-outcomes with caution and suggests that the present use of PCR-adjustment from paired blood samples in anti-malarial drug trials may overestimate assessment of drug efficacy in high transmission areas in Africa.The study is registered at http://www.clinicaltrials.gov with identifier NCT00336375.

Topics: Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Genetic Markers; Genetic Variation; Genotype; Genotyping Techniques; Humans; Infant; Malaria, Falciparum; Male; Merozoite Surface Protein 1; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Tanzania; Time Factors; Treatment Outcome

Combination therapy with artemesinin or non-artemesinin-based antimalarials (ACTs or NACTs) are known to retard the development and progression of drug resistance in Plasmodium falciparum (P. falciparum). The optimal antimalarial combinations in Africa are yet unknown. We evaluate the therapeutic efficacy and effects on gametocyte carriage of Artemether-Lumefantrine (AL) and Amodiaquine-Sulfalene/Pyrimethamine (ASP) in children with P. falciparum malaria in an endemic area. One-hundred and thirty-nine children aged ≤ 10 years with uncomplicated P. falciparum malaria were enrolled. The primary end points were adequate clinical and parasitological response (ACPR), late parasitological failure(LPF), late clinical failure (LCF) and early treatment failure (ETF). Polymerase chain reaction (PCR)-corrected cure rates on days 14-42 and gametocyte carriage rates were determined. Fever clearance time was significantly shorter (P = 0.009) with ASP, but parasite clearance time was similar with both regimens. Day 28 cure rates were 91.4 and 89.9% (PCR-corrected) for AL and ASP respectively. Both regimens were well tolerated. Overall, gametocyte carriage before and following treatment were similar. Both combinations were found effective and comparable for treatment of acute, uncomplicated, P. falciparum malaria.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Chloroquine; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Gametogenesis; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum; Polymerase Chain Reaction; Pyrimethamine; Sulfalene; Treatment Outcome

Controlled clinical trials have shown that a six-dose regimen of artemether-lumefantrine (AL) therapy for uncomplicated Plasmodium falciparum malaria results in cure rates >95% with good tolerability.. A prospective study was carried out to document the adherence to and acceptability of AL administration. This was undertaken in the context of the ALIVE study, a prospective, community-based, observational study in a rural, malaria-endemic area of Tanzania. Following microscopic confirmation of P. falciparum infection, the first AL dose was taken under supervision, with the subsequent five doses taken unsupervised at home. Patients were randomized to receive a home-based assessment close to the scheduled time for one of the unsupervised doses, but were blinded to which follow-up visit they had been allocated. A structured questionnaire was administered by trained staff and AL consumption was confirmed by inspection of blister packs.. A total of 552 patients were recruited of whom 352 (63.8%) were <13 years old. The randomization process allocated 112, 109, 110, 100 and 111 patients to a follow-up visit after doses 2, 3, 4, 5 and 6, respectively. For dose 2, 92.0% of patients (103/112) correctly took AL at 8 +/- 1 hours after dose 1. The remaining doses were taken within four hours of the correct time in 87-95% of cases. Nine patients (1.7%) missed one dose. Blister packs were available for inspection in 548 of cases (99.3%) and confirmed patient-reported data that the previous dose had been administered. Nearly all patients took AL with water (549/552 [99.5%]). Two patients (0.4%) took the drug with food. The dosing pictogram and clustering of tablets within the blister packs was considered helpful by 91.8% and 100.0% of patients, respectively. Overall, 87.1% of patients (481/552) found AL easier to take/administer than sulphadoxine-pyrimethamine (SP) and 87.7% (484/552) believed that AL was more effective than SP.. Factors contributing to adherence were likely to be helpful packaging, pictorial dosing instructions and patients' conviction that AL is effective.. Adherence to the dosing regimen and timing of AL administration was very good.

Topics: Administration, Oral; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Medication Adherence; Patient Acceptance of Health Care; Plasmodium falciparum; Prospective Studies; Rural Population; Surveys and Questionnaires; Tanzania; Treatment Outcome

Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria.. In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed.. The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29-96%) with crushed tablets and 65% (90% CI: 28-109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0-99.7%)] and was not related to food intake.. AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.

Topics: Acute Disease; Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biological Availability; Child; Child, Preschool; Diet; Drug Combinations; Ethanolamines; Female; Fluorenes; Food-Drug Interactions; Humans; Lumefantrine; Malaria, Falciparum; Male; Time Factors

The aim of this study was to investigate the efficacy of artemether-lumefantrine in treating uncomplicated Plasmodium falciparum malaria in four sentinel areas in Sudan with different malaria transmission (Damazin, Sinnar, and Kosti in the north, and Juba in the south).. World Health Organization protocol for assessing antimalarial drug efficacy in treating uncomplicated P. falciparum malaria was employed. A total of 2,139 patients were screened, and 771 had P. falciparum monoinfection. Only 291 met the enrollment criteria and gave written consent to be recruited in the study. Patients were treated with artemether-lumefantrine tablets in a six-dose regimen calculated according to body weight. Tablets were given at 0, 8, 24, 36, 48, and 60 h. Patients were followed up for 28 days.. A total of 291 patients were recruited to the study, of whom ten [3.4; 95% confidence interval (CI):1.8-6.4%] patients showed early treatment failure (ETF) or late clinical failure (LCF) and were excluded from further follow-up. Of the remaining 281 patients, 276 (98.2%; 95% CI: 95.7-99.3%) completed the 28-day follow-up. Of these, 274 (99.3%; 95% CI: 97.1-99.9%) had adequate clinical and parasitological response (ACPR), and two (0.7%; 95% CI: 0.13-2.9%) showed late parasitological failure (LPF) at days 21 and 28. The overall mean +/- standard deviation (SD) of parasitemia and fever clearance times were 36.4 (23.7) h and 34.6 (19.2) h, respectively. Mild and reversible adverse effects were reported by 11 patients (3.8%; CI: 2.0- 7.0%) and were relieved without the need for termination of drug therapy or supportive treatment.. Our findings showed that artemether-lumefantrine was an effective and safe drug for treating uncomplicated P. falciparum malaria in northern and southern Sudan.

Topics: Administration, Oral; Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Parasitemia; Sudan; Tablets; Time Factors; Treatment Outcome; Young Adult

To compare, in a phase IV trial, the efficacy and tolerability of artesunate-amodiaquine (Camoquin plus) dosed at 300 and 600 mg of amodiaquine per tablet to artemether-lumefantrine (Coartem) for the treatment of Plasmodium falciparum uncomplicated malaria in Ivory Coast and Senegal.. Multisite, randomised, open-labelled study in patients over the age of 7 years. The primary endpoint for efficacy was adequate clinical and parasitological response (ACPR) at day 28. The secondary endpoints were fever and parasite clearance and gametocyte carriage in each treatment group. Drug tolerability was assessed comparing adverse events and modification of biological parameters between D0 and D7. Data were analysed on an intention-to-treat and per protocol basis.. We included 322 patients; 316 patients completed the monitoring to D28 (155 in AS + AQ group and 161 in AL group). In ITT analysis, an ACPR corrected rate of 97.4% was observed in AS + AQ group versus 97% in AL group (P = 0.99). No parasite recrudescence was observed in AS + AQ arm. All patients in both groups had a fever and parasite clearance at D2. Gametocytes had disappeared by D14 in the AL group and by D21 in the AS + AQ group. No serious adverse events were observed. Minor adverse events were significantly more frequent in the AS + AQ arm. Biological parameters between D0 and D7 did not show any significant statistical variations except for anaemia.. This study demonstrates the efficacy and tolerability of AS + AQ for uncomplicated Plasmodium falciparum malaria treatment in African patients over the age of 7 years.

Topics: Adolescent; Adult; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Cote d'Ivoire; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Senegal; Statistics as Topic; Young Adult

A recent drug efficacy trial reported Coartem (artemether-lumefantrine) to be highly effective against Plasmodium falciparum in children less than 5 years of age in Papua New Guinea (PNG). In contrast, we have observed high levels of treatment failures in non-trial conditions in a longitudinal cohort study in the same age group in PNG. Recrudescences were confirmed by genotyping of three different marker genes to provide optimal discrimination power between parasite clones. After excluding genetic host factors by genotyping potentially relevant cytochrome P450 loci, the high number of treatment failures in our study is best explained by poor adherence to complex dosing regimens in combination with insufficient fat supplementation, which are both crucial parameters for the outcome of Coartem treatment. In contrast to the situation in classic drug trials with ideal treatment conditions, our field survey highlights potential problems with unsupervised usage of Coartem in routine clinical practice and under program conditions.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cohort Studies; Dietary Fats; Dietary Supplements; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Gene Expression Regulation; Genotype; Humans; Malaria, Falciparum; Papua New Guinea; Patient Compliance; Plasmodium falciparum; Protozoan Proteins

Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or third trimesters, but data on efficacy and safety in Africa were scarce. We aimed to assess whether artemether-lumefantrine was at least as efficacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda.. We did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemether-lumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confirmed by PCR. The non-inferiority margin was a difference in cure rate of 5%. Analysis of efficacy was for all randomised patients without study deviations that could have affected the efficacy outcome. This study was registered with ClinicalTrials.gov, number NCT00495508.. 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to follow-up and 25 were excluded from the analysis. At day 42, 137 (99.3%) of 138 patients taking artemether-lumefantrine and 122 (97.6%) of 125 taking quinine were cured-difference 1.7% (lower limit of 95% CI -0.9). There were 290 adverse events in the quinine group and 141 in the artemether-lumefantrine group.. Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and efficacy.. Médecins Sans Frontières and the European Commission.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Infectious; Quinine; Treatment Outcome; Uganda; Young Adult

To evaluate the effects of pre-season treatment with single dose of sulfadoxine-pyrimethamine (SP) or artemether-lumefantrine (AL) on subsequent malaria morbidity in under-fives.. A cohort of 156 children was enrolled for longitudinal follow-up. Children received curative therapy with SP or AL, and a third group received no treatment. Participants were home-visited twice a week with blood smears taken from children with fever (axillary T° ≥ 37.5 °C) or history of fever. To assess the time to re-infection, a blood film was also systematically obtained from pre-treated children every 2 weeks.. The mean time to the first malaria infection was 36 days in the SP arm and 26 days in the AL arm (P=0.006). The incidence density of malaria infection was similar in both groups (86.5%vs. 92.3%, P=0.52). The mean time to the first malaria episode was 47 days in the SP arm and 32 days in the AL arm (P<0.001). The incidence of malaria episodes was significantly higher in the group pre-treated with AL (45.7 per 1000 child days-at-risk CI 95% [35-56]) than in the control group (10.7 per 1000 child days-at-risk CI 95% [7-15]); P<0.001).. Our findings suggest that the radical clearance of parasitemia with AL may increase susceptibility to malaria infection and clinical malaria episodes.

Topics: Age Distribution; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child, Preschool; Disease Susceptibility; Drug Administration Schedule; Drug Combinations; Epidemiologic Methods; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Pyrimethamine; Recurrence; Seasons; Sex Distribution; Sulfadoxine; Treatment Outcome

Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) are efficacious regimens that have been widely adopted in sub-Saharan Africa. However, most study designs ignore the effects of these regimens on peripheral parasitaemia in the first 24 hours of therapy. The study protocol was designed to evaluate more closely the early effects and the standard measures of efficacies of these two regimens.. In an open label, randomized controlled clinical trial, children aged 12 months to 132 months were randomized to receive AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily) or artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) for three days. Peripheral blood smears were made hourly in the first 4 hours, 8 h, 16 h, 24 h, and daily on days 2-7, and on days 7, 14, 21, 28, 35, and 42 for microscopic identification and quantification of Plasmodium falciparum.. A total of 193 children were randomized to receive either AL (97) or AA (96). In children that received both medications, early response of peripheral parasitaemia showed that 42% of children who received AL and 36.7% of those who received AA had an immediate rise in peripheral parasitaemia (0-4 h after treatment) followed by a rapid fall. The rise in parasitaemia was significant and seems to suggest a mobilization of asexual parasites from the deep tissues to the periphery. Days 3, 7, 14, 28, and 42 cure rates in the per protocol (PP) population were > 90% in both groups of children. Both drug combinations were well tolerated with minimal side effects.. The study showed the high efficacy of AL and AA in Nigerian children. In addition the study demonstrated the mobilisation of asexual parasites from the deep to the periphery in the early hours of commencing ACT treatment in a subset of patients in both study groups. It is unclear whether the early parasite dynamics discovered in this study play any role in the development of drug resistance and thus it is important to further evaluate this discovery. It may be useful for studies investigating delay in parasite clearance of artemisinin derivatives as a way of monitoring the development of resistance to artemisinin to assess the early effects of the drugs on the parasites.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Plasmodium falciparum; Time Factors

Artemether-lumefantrine (AL) is a major and highly effective artemisinin-based combination therapy that is becoming increasingly important as a new first-line therapy against Plasmodium falciparum malaria. However, recrudescences occurring after AL treatment have been reported. Identification of drug-specific parasite determinants that contribute to treatment failures will provide important tools for the detection and surveillance of AL resistance.. The findings from a 42-day follow-up efficacy trial in Tanzania that compared AL with sulfadoxine-pyrimethamine (SP) were analyzed to identify candidate markers for lumefantrine tolerance/resistance in the chloroquine resistance transporter gene (pfcrt) and multidrug resistance gene 1 (pfmdr1). The findings were corroborated in vitro with genetically modified isogenic P. falciparum parasite lines.. Treatment with AL selected for the chloroquine-susceptible pfcrt K76 allele (P < .0001) and, to a lesser extent, the pfmdr1 N86 (P = .048) allele among recurrent infections. These genotypes were not selected during SP treatment. No pfmdr1 gene amplifications were observed. Isogenic pfcrt-modified parasite lines demonstrated a 2-fold increase in susceptibility to lumefantrine, which was directly attributable to the K76T mutation.. Our findings suggest that the pfcrt K76T mutation is a drug-specific contributor to enhanced P. falciparum susceptibility to lumefantrine in vivo and in vitro, and they highlight the benefit of using AL in areas affected by chloroquine-resistant P. falciparum malaria.

Topics: Alleles; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Membrane Transport Proteins; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Selection, Genetic; Sulfadoxine

The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance.. Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP) three-day (once daily for 3 days) regimen (N = 476) or AS-SMP 24-hour (0 h, 12 h, 24 h) regimen (N = 458) or artemether-lumefantrine (AL), the regular 6 doses regimen (N = 450). The primary objective was to demonstrate non-inferiority (using a margin of -6%) of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate.. The PCR corrected 28-day cure rate on the intention to treat (ITT) analysis population were: 96.0%(457/476) in the AS-SMP three-day group, 93.7%(429/458) in the AS-SMP 24-hour group and 92.0%(414/450) in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437) in the AS-SMP three-day group, 99.5%(416/419) in the AS-SMP 24-hour group and 99.7(391/394)% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea) which were slightly higher in the AS-SMP 24-hour group.. AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated.. NCT00484900 http://www.clinicaltrials.gov.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Pregnancy; Prospective Studies; Pyrimethamine; Sulfalene; Tablets; Treatment Outcome

Artemisinin-based combination therapy (ACT) is the treatment of choice for uncomplicated falciparum malaria. Artemether-lumefantrine (AL), a fixed dose co-formulation, has recently been approved for marketing in India, although it is not included in the National Drug Policy for treatment of malaria. Efficacy of short course regimen (4 x 4 tablets of 20 mg artemether plus 120 mg lumefantrine over 48 h) was demonstrated in India in the year 2000. However, low cure rates in Thailand and better plasma lumefantrine concentration profile with a six-dose regimen over three days, led to the recommendation of higher dose globally. This is the first report on the therapeutic efficacy of the six-dose regimen of AL in Indian uncomplicated falciparum malaria patients. The data generated will help in keeping the alternative ACT ready for use in the National Programme as and when required.. One hundred and twenty four subjects between two and fifty-five years of age living in two highly endemic areas of the country (Assam and Orissa) were enrolled for single arm, open label prospective study. The standard six-dose regimen of AL was administered over three days and was followed-up with clinical and parasitological evaluations over 28 days. Molecular markers msp-1 and msp-2 were used to differentiate the recrudescence and reinfection among the study subjects. In addition, polymorphism in pfmdr1 was also carried out in the samples obtained from patients before and after the treatment.. The PCR corrected cure rates were high at both the sites viz. 100% (n = 53) in Assam and 98.6% (n = 71) in Orissa. The only treatment failure case on D7 was a malnourished child. The drug was well tolerated with no adverse events. Patients had pre-treatment carriage of wild type codons at positions 86 (41.7%, n = 91) and 184 (91.3%, n = 91) of pfmdr1 gene.. AL is safe and effective drug for the treatment of acute uncomplicated falciparum malaria in India. The polymorphism in pfmdr1 gene is not co-related with clinical outcome. However, treatment failure can also occur due to incomplete absorption of the drug as is suspected in one case of failure at D7 in the study. AL can be a viable alternative of artesunate plus sulphadoxine/pyrimethamine (AS + SP), however, the drug should be used rationally and efficacy needs to be monitored periodically.

Topics: Adolescent; Adult; Amplified Fragment Length Polymorphism Analysis; Animals; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; India; Malaria, Falciparum; Male; Merozoite Surface Protein 1; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Protozoan Proteins; Recurrence; Treatment Outcome; Young Adult

Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast.. We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection.. Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance.. These data suggest that Arco could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Cote d'Ivoire; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Recurrence; Treatment Outcome

To compare the effectiveness of oral quinine with that of artemether-lumefantrine in treating uncomplicated malaria in children.. Randomised, open label effectiveness study.. Outpatient clinic of Uganda's national referral hospital in Kampala.. 175 children aged 6 to 59 months with uncomplicated malaria.. Participants were randomised to receive oral quinine or artemether-lumefantrine administered by care givers at home.. Primary outcomes were parasitological cure rates after 28 days of follow-up unadjusted and adjusted by genotyping to distinguish recrudescence from new infections. Secondary outcomes were adherence to study drug, presence of gametocytes, recovery of haemoglobin concentration from baseline at day 28, and safety profiles.. Using survival analysis the cure rate unadjusted by genotyping was 96% for the artemether-lumefantrine group compared with 64% for the quinine group (hazard ratio 10.7, 95% confidence interval 3.3 to 35.5, P=0.001). In the quinine group 69% (18/26) of parasitological failures were due to recrudescence compared with none in the artemether-lumefantrine group. The mean adherence to artemether-lumefantrine was 94.5% compared with 85.4% to quinine (P=0.0008). Having adherence levels of 80% or more was associated with a decreased risk of treatment failure (0.44, 0.19 to 1.02, P=0.06). Adverse events did not differ between the two groups.. The effectiveness of a seven day course of quinine for the treatment of uncomplicated malaria in Ugandan children was significantly lower than that of artemether-lumefantrine. These findings question the advisability of the recommendation for quinine therapy for uncomplicated malaria in Africa.. ClinicalTrials.gov NCT00540202.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Medication Adherence; Quinine; Treatment Outcome

Artemisinin-based combination therapies are now widely recommended as first-line treatment for uncomplicated malaria. However, which therapies are optimal is a matter of debate. We aimed to compare the short- and longer-term efficacy of 2 leading therapies in a cohort of young Ugandan children.. A total of 351 children aged 6 weeks to 12 months were enrolled and followed up for up to 1 year. Children who were at least 4 months of age, weighted at least 5 kg, and had been diagnosed as having their first episode of uncomplicated malaria were randomized to receive artemether-lumefantrine or dihydroartemisinin-piperaquine. The same treatment was given for all subsequent episodes of uncomplicated malaria. Recrudescent and new infections were distinguished by polymerase chain reaction genotyping. Outcomes included the risk of recurrent malaria after individual treatments and the incidence of malaria treatments for individual children after randomization.. A total of 113 children were randomized to artemether-lumefantrine and 119 to dihydroartemisinin-piperaquine, resulting in 320 and 351 treatments for uncomplicated falciparum malaria, respectively. Artemether-lumefantrine was associated with a higher risk of recurrent malaria after 28 days (35% vs 11%; P = .001]). When the duration of follow-up was extended, differences in the risk of recurrent malaria decreased such that the overall incidence of malaria treatments was similar for children randomized to artemether-lumefantrine, compared with those randomized to dihydroartemisinin-piperaquine (4.82 vs 4.61 treatments per person-year; P = .63). The risk of recurrent malaria due to recrudescent parasites was similarly low in both treatment arms.. Artemether-lumefantrine and dihydroartemisinin-piperaquine were both efficacious and had similar long-term effects on the risk of recurrent malaria. Clinical trials registration. NCT00527800.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Quinolines; Treatment Outcome; Uganda

Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy.. We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized for treatment with AQ-SP, AS-AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro susceptibility to monodesethylamodiaquine (MDAQ) was measured with a histidine-rich protein 2-based enzyme-linked immunosorbent assay, and potential resistance-mediating polymorphisms in pfmdr1 were evaluated.. Parasites collected from patients treated with AQ-SP or AS-AQ within the prior 12 weeks were less susceptible to MDAQ (n = 18; mean of the median inhibitory concentration [IC(50)], 62.9 nmol/L; range, 12.7-158.3 nmol/L) than were parasites from those not treated within 12 weeks (n = 43; mean IC(50), 37.5 nmol/L; range, 6.3-184.7 nmol/L; P=.009) or only from those patients in the treatment arm that did not receive AQ (n = 12; mean IC(50), 28.8 nmol/L; range, 6.3-121.8 nmol/L; P = .004). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr1 86Y and 1246Y) increased after AQ therapy, although differences were not statistically significant.. Prior therapy selected for diminished response to MDAQ, which suggests that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr1.

Topics: Amino Acid Sequence; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Cohort Studies; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Molecular Sequence Data; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Pyrimethamine; Sequence Alignment; Sulfadoxine; Uganda

Artemisinin combination therapy has become the standard of care for uncomplicated malaria in most of Africa. However, there is limited data on the safety and tolerability of these drugs, especially in young children and patients co-infected with HIV.. A longitudinal, randomized controlled trial was conducted in a cohort of HIV-infected and uninfected children aged 4-22 months in Tororo, Uganda. Participants were randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) upon diagnosis of their first episode of uncomplicated malaria and received the same regimen for all subsequent episodes. Participants were actively monitored for adverse events for 28 days and then passively for up to 63 days after treatment. This study was registered in ClinicalTrials.gov (registration # NCT00527800).. A total of 122 children were randomized to AL and 124 to DP, resulting in 412 and 425 treatments, respectively. Most adverse events were rare, with only cough, diarrhoea, vomiting, and anaemia occurring in more than 1% of treatments. There were no differences in the risk of these events between treatment groups. Younger age was associated with an increased risk of diarrhoea in both the AL and DP treatment arms. Retreatment for malaria within 17-28 days was associated with an increased risk of vomiting in the DP treatment arm (HR = 6.47, 95% CI 2.31-18.1, p < 0.001). There was no increase in the risk of diarrhoea or vomiting for children who were HIV-infected or on concomitant therapy with antiretrovirals or trimethoprim-sulphamethoxazole prophylaxis.. Both AL and DP were safe and well tolerated for the treatment of uncomplicated malaria in young HIV-infected and uninfected children.. ClinicalTrials.gov: NCT00527800; http://clinicaltrials.gov/ct2/show/NCT00527800.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; HIV Infections; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Male; Quinolines; Risk Factors; Treatment Outcome; Uganda

Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.. A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.. Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.. This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.. Current Controlled Trials Identifier ISRCTN37517549.

Topics: Amodiaquine; Anorexia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Muscle Weakness; Pyrimethamine; Single-Blind Method; Sulfadoxine; Uganda

Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments.. Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted.. Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up.. AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation.. NCT 00406146 http://www.clinicaltrials.gov.

Topics: Adolescent; Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Ghana; Humans; Infant; Leukocyte Count; Malaria, Falciparum; Male; Neutrophils; Plasmodium falciparum; Polymerase Chain Reaction; Treatment Outcome

Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria.. We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97.5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763.. 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97.8% (95% CI 96.3-99.2) in the group on dispersible formulation and 98.5% (97.4-99.7) in the group on crushed formulation. The lower bound of the one-sided 97.5% CI was -2.7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen.. A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile.

Topics: Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chemistry, Pharmaceutical; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Tablets; Treatment Outcome

Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.. In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.. Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.. Current controlled trials ISRCTN36463274.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Kenya; Malaria, Falciparum; Male; Microscopy; Parasitemia; Plasmodium falciparum; Quinolines; Self-Sustained Sequence Replication; Treatment Outcome

The six-dose regimen of artemether-lumefantrine (AL) is now considered the gold standard for the treatment of uncomplicated Plasmodium falciparum malaria. There are few reports evaluating co-artemether in very young Nigerian infants and children. Results of the evaluation of the six-dose regimen in very young infants and children in Nigeria are presented in this report.. As part of a larger African study, this open label, non-comparative trial, assessed the efficacy and safety of six-dose regimen of AL tablets in 103 Nigerian infants and children weighing between five and 25 kg suffering from acute uncomplicated malaria. Treatment was administered under supervision over three days with children as in-patients. 12-lead ECG tracings were taken pre-treatment and at day 3.. Ninety-three infants and children completed the study as stipulated by the protocol. Mean fever and parasite clearance times for the intent to treat population (ITT) were 24.9 h +/- (1.28) and 26 h +/- (4.14) and the corresponding figures for the per-protocol population (PP) were 19.24 h +/- 13.9 and 25.62 h +/- 11.25 respectively. Day 14 cure rates for the ITT and PP were 95.1% and 100% respectively while day 28 cure rates were 91.3% and 95.7% respectively. The overall PCR corrected day 28 cure rate was 95.1% for the ITT. The six-dose regimen of AL was well tolerated with no drug-related serious adverse events. Although six patients recorded a QTc prolongation of > 60 ms on D3 over D0 recording, no patient recorded a QTc interval > 500 ms.. The six-dose regimen of AL tablets is safe and effective for the treatment of acute uncomplicated malaria in Nigerian infants and children weighing between five and 25 kg.. NCT00709969.

Topics: Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum; Time Factors; Treatment Outcome

Numerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria.. A randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam) or AL (Coartem). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews.. Adequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00-5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05).. Unobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.

Topics: Amodiaquine; Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Ghana; Humans; Infant; Malaria, Falciparum; Patient Acceptance of Health Care; Plasmodium falciparum; Treatment Outcome

Artemether/lumefantrine (AL) has been adopted as the treatment of choice for uncomplicated malaria in Kenya and other countries in the region. Six-dose artemether/lumefantrine tablets are highly effective and safe for the treatment of infants and children weighing between five and 25 kg with uncomplicated Plasmodium falciparum malaria. However, oral paediatric formulations are urgently needed, as the tablets are difficult to administer to young children, who cannot swallow whole tablets or tolerate the bitter taste of the crushed tablets.. A randomized, controlled, open-label trial was conducted comparing day 28 PCR corrected cure-rates in 245 children aged 6-59 months, treated over three days with either six-dose of artemether/lumefantrine tablets (Coartem) or three-dose of artemether/lumefantrine suspension (Co-artesiane) for uncomplicated falciparum malaria in western Kenya. The children were followed-up with clinical, parasitological and haematological evaluations over 28 days.. Ninety three percent (124/133) and 90% (121/134) children in the AL tablets and AL suspension arms respectively completed followed up. A per protocol analysis revealed a PCR-corrected parasitological cure rate of 96.0% at Day 28 in the AL tablets group and 93.4% in the AL suspension group, p = 0.40. Both drugs effectively cleared gametocytes and were well tolerated, with no difference in the overall incidence of adverse events.. The once daily three-dose of artemether-lumefantrine suspension (Co-artesiane(R)) was not superior to six-dose artemether-lumefantrine tablets (Coartem) for the treatment of uncomplicated malaria in children below five years of age in western Kenya.

Topics: Analysis of Variance; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Fluorenes; Follow-Up Studies; Humans; Infant; Kenya; Malaria, Falciparum; Plasmodium falciparum; Suspensions; Tablets; Treatment Outcome

Malaria infection during pregnancy is a major public health problem. Due to increasing resistance to Chloroquine and Sulphadoxine/Pyrimethamine, the Ugandan national policy on malaria treatment was changed in 2005 to Artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The policy recommends assessment of safety and efficacy of alternative drugs for treatment of uncomplicated malaria. We compared the efficacy and safety of Artemether-Lumefantrine (Coartem) and Chlorproguanil-Dapsone (Lapdap) in the management of uncomplicated malaria in pregnancy.. We enrolled 110 pregnant women in the second and third trimester of pregnancy who presented to Mulago hospital, Uganda, with uncomplicated malaria. The study design was an open-label randomized clinical trial. Participants were randomized to receive either Artemether-Lumefantrine (Coartem 20 mg/120 mg) orally or Chlorproguanil-Dapsone (Lapdap) orally for 3 consecutive days. Primary endpoints were clinical and parasitological response assessed on days 0, 1, 2, 4, 7, 14 and 28. Adverse effects, clinical response (treatment failure) and parasitological response were compared. Analysis was by intention to treat.. Of the 100 women who completed the study, there was no statistically significant difference in clinical and parasitological response by Day 4. The mean fever clearance time 3.0 days with Lapdap versus 2.5 days with Coartem was comparable. Likewise, mean parasite clearance time of 2.4 and 2.2 days for Lapdap and Coartem respectively was comparable. The adverse effects were comparable between the two groups.. Artemether-Lumefantrine and Chlorproguanil-Dapsone have high and comparable cure rates and similar safety profiles when used for treatment of uncomplicated malaria in pregnancy.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Dapsone; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Uganda; Young Adult

Although artemisinin and its derivatives are widely used for the treatment of malaria, they also have antischistosomal activity. In a small study in eastern Sudan, the effects of the treatment of uncomplicated, Plasmodium falciparum malaria with artesunate-sulfamethoxypyrazine-pyrimethamine (AS-SMP) and artemether-lumefantrine (AT-LU) on co-infections with Schistosoma mansoni were therefore investigated. Faecal samples from 14 of the 306 patients screened on presentation, at the start of a clinical trial of antimalarial treatment, were found to contain Schistosoma mansoni eggs. For the treatment of their malaria, the 14 egg-positive cases, who were aged 6-40 years (mean = 13.7 years), were each subsequently treated with three tablets of a fixed combination of AS-SMP, with a 12-h (six patients) or 24-h interval (five patients) between each tablet, or with six doses of AT-LU given over 3 days. When checked 28 and 29 days after the initiation of treatment, all 14 patients were found stool-negative for schistosome eggs. These results indicate that AS-SMP and AT-LU are currently very effective treatments not only for uncomplicated, P. falciparum malaria but also for S. mansoni infections.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Drug Combinations; Drug Therapy, Combination; Endemic Diseases; Ethanolamines; Feces; Fluorenes; Humans; Malaria, Falciparum; Parasite Egg Count; Pyrimethamine; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; Sesquiterpenes; Sudan; Sulfalene

The efficacy and safety of artemether-lumefantrine for the treatment of malaria in nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Time Factors; Travel; Treatment Outcome

Coartem is a fixed-dose combination of artemether-lumefantrine that, given in six doses, provides effective treatment for children with uncomplicated Plasmodium falciparum infection in areas with highly endemic and multidrug-resistant malaria. In Rwanda since 2001, amodiaquine+sulfadoxine-pyrimethamine (AQ+SP) has been the first-line treatment, but resistance to this combination has rapidly emerged and spread. Coartem was considered as a possible alternative, and a randomised, open-label, clinical trial to test its safety, tolerability and efficacy was carried out in 2004-2005. Five hundred children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to AQ+SP or Coartem. Patients were followed up until day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Adequate clinical and parasitological response (ACPR) was significantly higher in children treated with Coartem than in those treated with AQ+SP: the PCR-adjusted 28-day ACPR was 96.68% for Coartem and 79.35% for AQ+SP. Both treatments rapidly cleared parasitaemia and fever, although parasite clearance was significantly faster in children treated with Coartem. Mean packed cell volume increased in all patients, with no significant differences between treatments. Coartem proved to be more efficacious than AQ+SP, with a good safety and tolerability profile.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Pyrimethamine; Sulfadoxine; Treatment Outcome

An open randomized controlled study of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out in 181 children. In 79 children, the hepatomegaly reduction ratios (HRR) and the speed of resolution of hepatomegaly, the hepatomegaly resolution rates (HRSR), were calculated and compared between the two treatment groups. HRR and HRSR were similar in the two treatment groups. HRSR was 71% and 62% in AL- and ASP-treated children, respectively, 14 days after commencing treatment. There was no significant correlation between HRR and parasite reduction ratio in the same patient. In children in whom parasitaemia cleared and hepatomegaly resolved within 14 days, recurrence of parasitaemia was associated with reoccurrence of hepatomegaly, suggesting that the propensity for recurrence of infection drives the malaria-attributable hepatomegaly in children from this endemic area. Combination therapy may provide additional beneficial effects on pathophysiological processes and changes associated with falciparum malaria by rapid clearing of asexual parasitaemia and reducing the propensity for recurrence of infection.

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Hepatomegaly; Humans; Malaria, Falciparum; Male; Pyrimethamine; Sulfalene; Time Factors; Treatment Outcome

We assessed the influence that consecutive-day blood sampling, compared with single-day blood sampling, had on polymerase chain reaction (PCR)-adjusted parasitological cure after stepwise genotyping of merozoite surface proteins 2 (msp2) and 1 (msp1) in 106 children in Tanzania who had uncomplicated falciparum malaria treated with either sulfadoxine-pyrimethamine or artemether-lumefantrine; 78 of these children developed recurrent parasitemia during the 42-day follow-up period. Initial msp2 genotyping identified 27 and 33 recrudescences by use of single- and consecutive-day sampling, respectively; in subsequent msp1 genotyping, 17 and 21 of these episodes, respectively, were still classified as recrudescences; these results indicate a similar sensitivity of the standard single-day PCR protocol--that is, 82% (27/33) and 81% (17/21), in both genotyping steps. Interpretation of PCR-adjusted results will significantly depend on methodology.

Topics: Animals; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; DNA, Protozoan; Drug Combinations; Ethanolamines; Fluorenes; Genotype; Humans; Malaria, Falciparum; Merozoite Surface Protein 1; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Pyrimethamine; Recurrence; Sulfadoxine; Tanzania

Bangladesh faces increasing levels of chloroquine resistance, and drug sensitivity to sulfadoxine-pyremethamine is already compromised. Therefore, the Ministry of Health recently changed the national treatment guidelines to artemisinin-based combination therapies. The purpose of this study was to determine the baseline therapeutic efficacy of artemether-lumefantrine used as a six-dose regimen for the treatment of uncomplicated Plasmodium falciparum malaria. Sixty-seven patients were enrolled in the study; the cure rate in a 42-day follow-up after an adjustment by polymerase chain reaction was 94.3%. The treatment led to rapid fever (mean +/- SD = 25.82 +/- 12.14 hours) and parasite (30.36 +/- 19.43 hours) clearance. These data suggest that artemether-lumefantrine is a highly efficacious and well-tolerated treatment for uncomplicated P. falciparum malaria in Bangladesh.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bangladesh; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum

Artemisinin-based combination regimens are widely advocated for malarial treatment, but other effective regimens might be cheaper and more readily available. Our aim was to compare the risk of recurrent parasitaemia in patients given artemether-lumefantrine with that in those given amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated malaria.. We enrolled 521 patients aged 6 months or older with uncomplicated falciparum malaria in Bobo-Dioulasso, Burkina Faso. Patients were randomly assigned to receive standard doses of either artemether-lumefantrine (261) or amodiaquine plus sulfadoxine-pyrimethamine (260) for 3 days. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. The study is registered at controlled-trials.gov with the identifier ISRCTN54261005.. Of enrolled patients, 478 (92%) completed the 28-day study. The risk of recurrent symptomatic malaria was lowest in the group given amodiaquine plus sulfadoxine-pyrimethamine (1.7%vs 10.2%; risk difference 8.5%; 95% CI 4.3-12.6; p=0.0001); as was the risk of recurrent parasitaemia (4.7%vs 15.1%; 10.4%; 5.1-15.6; p=0.0002). Nearly all recurrences were due to new infections. Recrudescences were four late treatment failures with artemether-lumefantrine and one early treatment failure with amodiaquine plus sulfadoxine-pyrimethamine. Both regimens were safe and well tolerated, with pruritus more common with amodiaquine plus sulfadoxine-pyrimethamine than with artemether-lumefantrine. Each regimen selected for new isolates with mutations that have been associated with decreased drug susceptibility.. Amodiaquine plus sulfadoxine-pyrimethamine was more effective than was artemether-lumefantrine for the treatment of uncomplicated malaria. For regions of Africa where amodiaquine plus sulfadoxine-pyrimethamine continues to be effective, this less expensive and more available regimen should be considered as an alternative to blanket recommendations for artemisinin-based combination treatment for malaria.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Parasitemia; Pyrimethamine; Recurrence; Sulfadoxine; Treatment Outcome

Artemether-lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the dose-response relationship between coadministration of fat and relative lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption.. We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration-time curve (AUC) for lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3- to 4-week washout period in-between.. A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat).. Coadministration of artemether-lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.

Topics: Absorption; Administration, Oral; Adult; Antimalarials; Area Under Curve; Artemether, Lumefantrine Drug Combination; Artemisinins; Biological Availability; Cross-Over Studies; Dietary Supplements; Dose-Response Relationship, Drug; Drug Combinations; Ethanolamines; Fasting; Female; Fluorenes; Food-Drug Interactions; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Soy Milk

Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether-lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance.. In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration-time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles.. Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC((0-->infinity)) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114-5781) microg/ml h, compared with 432 (308-992) microg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84-100) in the six-dose arm and 85% (70-100) in the three-dose arm (P = 0.3).. Artemether-lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat.

Topics: Absorption; Administration, Oral; Adolescent; Adult; Antimalarials; Area Under Curve; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Treatment Outcome

The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax.. 774 patients in southern Papua, Indonesia, with slide-confirmed malaria were randomly assigned to receive either artemether-lumefantrine or dihydroartemisinin-piperaquine and followed up for at least 42 days. The primary endpoint was the overall cumulative risk of parasitological failure at day 42 with a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, trial number 00157833.. Of the 754 evaluable patients enrolled, 466 had infections with P falciparum, 175 with P vivax, and 113 with a mixture of both species. The overall risk of failure at day 42 was 43% (95% CI 38-48) for artemether-lumefantrine and 19% (14-23) for dihydroartemisinin-piperaquine (hazard ratio=3.0, 95% CI 2.2-4.1, p<0.0001). After correcting for reinfections, the risk of recrudescence of P falciparum was 4.4% (2.6-6.2) with no difference between regimens. Recurrence of vivax occurred in 38% (33-44) of patients given artemether-lumefantrine compared with 10% (6.9-14.0) given dihydroartemisinin-piperaquine (p<0.0001). At the end of the study, patients receiving dihydroartemisinin-piperaquine were 2.0 times (1.2-3.6) less likely to be anaemic and 6.6 times (2.8-16) less likely to carry vivax gametocytes than were those given artemether-lumefantrine.. Both dihydroartemisinin-piperaquine and artemether-lumefantrine were safe and effective for the treatment of multidrug-resistant uncomplicated malaria. However, dihydroartemisinin-piperaquine provided greater post-treatment prophylaxis than did artemether-lumefantrine, reducing P falciparum reinfections and P vivax recurrences, the clinical public-health importance of which should not be ignored.

Topics: Adolescent; Adult; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Diarrhea; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple; Ethanolamines; Female; Fluorenes; Humans; Indonesia; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Prospective Studies; Quinolines; Recurrence; Sesquiterpenes; Treatment Outcome; Urticaria; Vomiting

Combination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas.. To compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria.. Single-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic.. Study participants were randomized to receive 1 of 3 combination therapies (amodiaquine plus sulfadoxine-pyrimethamine, amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes.. 28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs.. Of enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P< or =.008 for all pairwise comparisons, except amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing.. Artemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures.. isrctn.org Identifier: ISRCTN37517549.

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sesquiterpenes; Single-Blind Method; Sulfadoxine; Treatment Outcome; Uganda; Urban Population

The treatment efficacy and effects of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) on gametocyte carriage were evaluated in 181 children < or = 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug combination. All children recovered clinically. Fever clearance times were similar. The rate of P. falciparum reappearance (recrudescence or re-infection) between two and six weeks after the start of therapy was significantly higher in AL-treated children (P = 0.01). Parasite clearance was significantly faster in children treated with AL (mean +/- SD = 1.7 +/- 0.6 days, 95% confidence interval = 1.58 - 1.83, P = 0.0001) but the polymerase chain reaction-corrected cure rate (90 of 91 versus 84 of 90) and the rate of resolution of malaria-related anemia two weeks after treatment began (45 of 50 versus 33 of 46) were higher in children treated with ASP. Gametocyte carriage rates were similar. Both regimens were well tolerated. Artemether-lumefantrine clears parasitemia more rapidly than ASP but both combinations are effective in treatment of uncomplicated P. falciparum malaria in Nigerian children.

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sulfalene

Because available data suggest that resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) is increasing in Nepal, an open-label, parallel-group efficacy/safety study was conducted in 99 Nepalese patients with uncomplicated falciparum malaria randomized 2:1 to artemetherlumefantrine (AL) or SP. Efficacy was assessed from clinical and microscopic evidence of treatment failure. Four SP-treated patients (12.1%; 95% CI, 4.0-29.1%) redeveloped parasitemia during the 28-day follow-up versus 0% (95% CI, 0-6.9%) in the AL group (P = 0.011), a difference that was confirmed by polymerase chain reaction (PCR) analysis of parasite DNA. PCR detected an additional six patients (two SP and four AL) with sub-microscopic gametocytemia or breakthrough parasitemia between Days 14 and 28, suggesting that AL efficacy was lower than estimated by microscopy. Dhfr and dhps mutations were not associated with outcome. AL is more effective than SP for uncomplicated malaria in Nepal, but regular monitoring of its efficacy should be carried out if this combination therapy is introduced.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Nepal; Plasmodium falciparum; Plasmodium vivax; Pyrimethamine; Sulfadoxine; Treatment Outcome

Combination antimalarial therapy is advocated to improve treatment efficacy and limit selection of drug-resistant parasites. We compared the efficacies of 3 combination regimens in Bobo-Dioulasso, Burkina Faso: amodiaquine plus sulfadoxine-pyrimethamine, which was recently shown to be highly efficacious at this site; artemether-lumefantrine, the new national first-line antimalarial regimen; and dihydroartemisinin-piperaquine (DP), a newer regimen.. We enrolled 559 patients >or=6 months of age with uncomplicated Plasmodium falciparum malaria and randomized them to the 3 regimens. We analyzed the risk of recurrent parasitemia by day 28 and day 42, both unadjusted and adjusted by PCR methods to distinguish recrudescence and new infection.. Complete data were available for 517 (92.5%) of the enrolled subjects. Early treatment failures occurred in 5 patients treated with amodiaquine plus sulfadoxine-pyrimethamine and in 2 patients each treated with the other regimens. The day 28 risk of recurrent parasitemia, unadjusted by genotyping, was significantly higher for patients receiving artemether-lumefantrine than for patients receiving amodiaquine plus sulfadoxine-pyrimethamine (20.1% vs. 6.2%; risk difference, 13.8%; 95% confidence interval, 7.0%-20.7%) or dihydroartemisinin-piperaquine (20.1% vs. 2.2%; risk difference, 17.9%; 95% confidence interval, 11.6%-24.1%). Similar differences were seen for children <5 years of age (54% of the study population) and when outcomes were extended to 42 days. Significant differences were not seen between outcomes for patients receiving amodiaquine plus sulfadoxine-pyrimethamine and outcomes for those receiving dihydroartemisinin-piperaquine. Recrudescences were uncommon (occurring in <5% of patients) in all treatment groups. No serious adverse events were noted.. All regimens were highly efficacious in clearing infection, but considering the risks of recurrent malaria after therapy, the amodiaquine plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine regimens were more efficacious than the artemether-lumefantrine regimen (the new national regimen in Burkina Faso) for the treatment of uncomplicated P. falciparum malaria.

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Pyrimethamine; Quinolines; Sulfadoxine

From 2001 to 2003, anti-malarial combination coartem and fansimef, recommended by WHO, were used to treat falciparum malaria in Mali, 28 cases in each group. The mean fever clearance time, mean asexual parasite clearance time and the cure rate in 28 days were 35.3 +/- 6. 4, 34.7 +/- 6.9 hours and 100% respectively in coartem group, and 32. 6 +/- 5.8, 36.8 +/- 5.3 hours and 96.4% respectively in the fansimef group, with no significant difference between the two groups (P > 0.05).

Topics: Abdominal Pain; Adolescent; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fever; Fluorenes; Humans; Malaria, Falciparum; Male; Mali; Mefloquine; Nausea; Pyrimethamine; Skin; Sulfadoxine; Time Factors; Treatment Outcome

To determine the efficacy of artemether-lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai-Cambodian border.. Two studies were conducted to monitor the efficacy of artemether-lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow-up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with artemether-lumefantrine.. A total of 190 patients were included: 55 were treated with artemether-lumefantrine in 2002 (AL2002), 80 with artemether-lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per-protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The artemether-lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated.. Treatment failure cases of artemether-lumefantrine are most probably because of low levels of lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Dietary Supplements; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Parasitic Sensitivity Tests; Plasmodium falciparum; Sesquiterpenes; Treatment Failure; Treatment Outcome

Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.

Topics: Acute Disease; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Heart Rate; Hematologic Tests; Humans; Infant; Kenya; Malaria, Falciparum; Male; Nigeria; Parasite Egg Count; Sesquiterpenes; Sex Distribution; Tanzania; Time Factors; Treatment Outcome

To observe the efficacy and safety of co-artemether and one of its components benflumetol (two formulations) in the treatment of patients with falciparum malaria.. Adopting double-blining, randomization and comparative method, all patients were hospitalized and observed for 28 days after treatment.. Of 150 patients, 51 patients were treated with co-artemether group(A), 50-patients were treated with benflumetol tablet group(B), 49 patients were freated with benflumetol capsule group(C). The mean fever clearance times for groups A, B and C were 17.1 +/- 8.6, 34.0 +/- 23.2 and 29.4 +/- 24.9 hours, respectively; the mean parasite clearance times were 29.7 +/- 8.9, 51.6 +/- 14.1 and 54.7 +/- 17.4 hours respectively; the cure rates in 28 days for groups A, B and C were 98.2%, 92.0% and 95.8%, respectively. No apparent side-effect was observed.. Co-artemether and benflumetol (2 formulations) are effective for the treatment of patients with falciparum malaria but co-artemether is more effective than benflumetol (2 formulations) in terms of controlling symptoms and killing parasites.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Sesquiterpenes

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Double-Blind Method; Drug Combinations; Electrocardiography; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Polymerase Chain Reaction; Sesquiterpenes; Time Factors

The new oral fixed combination artemether-lumefantrine (CGP 56697) has proved to be an effective and well-tolerated treatment of multi-drug resistant Plasmodium falciparum malaria, although cure rates using the four-dose regimen have been lower than with the currently recommended alternative of artesunate-mefloquine. Two six-dose schedules (total adult dose = 480 mg of artemether and 2,880 mg of lumefantrine) were therefore compared with the previously used four-dose regimen (320 mg of artemether and 1,920 mg of lumefantrine) in a double-blind trial involving 359 patients with uncomplicated multidrug-resistant falciparum malaria. There were no differences between the three treatment groups in parasite and fever clearance times, and reported adverse effects. The two six-dose regimens gave adjusted 28-day cure rates of 96.9% and 99.12%, respectively, compared with 83.3% for the four-dose regimen (P < 0.001). These six-dose regimens of artemether-lumefantrine provide a highly effective and very well-tolerated treatment for multidrug-resistant falciparum malaria.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Resistance, Multiple; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Recurrence; Sesquiterpenes; Thailand

CGP 56697 (Riamet) is a new oral anti-malarial drug composed of artemether and lumefantrine (benflumetol) which combines the fast, short-acting artemether for rapid parasite clearance with the prolonged action of lumefantrine for intended radical cure. In this double-blind, comparative trial, the efficacy and tolerability of CGP 56697, given as a course of 4 x 4 tablets over 48 h, was compared to halofantrine, given as 3 x 2 tablets over 12 h with a second course 1 week later. Patients (mostly non-immune) with acute, uncomplicated Plasmodium falciparum infection were randomly assigned to either CGP 56697 (n = 51) or halofantrine (n = 52). CGP 56697 proved superior with respect to parasite clearance time (median 32 vs. 48 h, P < 0.001) and parasite reduction at 24 h (median 99.7 vs. 89.6%, P < 0.001) with a non-significant difference in resolution of fever (median 24 vs. 32 h, P = 0.835). However, a 28-day cure rate of 82% was observed for CGP 56697 and 100% for halofantrine. Significant QTc prolongations (> 30 ms) were seen 6-12 h after halofantrine intake but not after CGP 56697 intake. CGP 56697 is an effective, well-tolerated treatment for uncomplicated falciparum malaria but for this dosing regimen the recrudescence rate is unacceptablyhigh (18%). For travellers contracting malaria abroad, we propose a six-dose regimen of CGP 56697 over 3 days.

Topics: Adolescent; Adult; Africa; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; France; Humans; Malaria, Falciparum; Male; Middle Aged; Netherlands; Parasite Egg Count; Phenanthrenes; Plasmodium falciparum; Sesquiterpenes; Time Factors; Travel; Tropical Climate

The pharmacokinetics of benflumetol as a fixed combination, artemether-benflumetol (CGP 56697), following three regimens [regimen A: four tablets at 0, 8, 24 and 48 h (320 mg artemether, 1,920 mg benflumetol); regimen B: two tablets at 0, 8, 24 and 48 h (160 mg artemether, 960 mg benflumetol); regimen C: four tablets at 0, 8 and 24 h (240 mg artemether, 1,440 mg benflumetol)] were investigated in 39 patients with acute uncomplicated falciparum malaria. All patients showed a rapid initial response with a median parasite clearance time of 40, 41 and 39.5 h and a fever clearance time of 27.8, 32 and 24.5 h for regimens A, B and C, respectively. In nine patients (two, four and three patients in regimens A, B and C, respectively), however, parasitemia reappeared in the peripheral blood smear between days 9 and 23. The pharmacokinetics of benflumetol were highly variable, with coefficients of variation in pharmacokinetic parameters ranging from 14.9% to 144%. Absorption and elimination of benflumetol were relatively slow. Median Cmax per dose (first dose) was significantly higher in regimen B (6.29 ng/ml/mg dose) than in regimen A (2.6 ng/ml/mg dose) and regimen C (3.06 ng/ml/mg dose). Mean T1/2z in regimen C (2.65 h) was significantly shorter than in regimen A (4.5 h) and regimen B (3.89 h). In patients on regimens A and B who showed a sensitive response, plasma concentrations of benflumetol were significantly higher than in those with treatment failure.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Random Allocation; Sesquiterpenes; Thailand; Time Factors

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Pyrimethamine; Sesquiterpenes; Sulfadoxine

To test the efficacy of a new compound drug (CGP 56697) against acute, uncomplicated falciparum malaria.. Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups.. Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time.. The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.

Topics: Acute Disease; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Recurrence; Sesquiterpenes; Tanzania; Time Factors; Treatment Outcome

A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.

Topics: Acute Disease; Administration, Oral; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Chloroquine; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Sesquiterpenes; Tanzania; Treatment Outcome

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Ethanolamines; Fluorenes; Gambia; Humans; Infant; Lumefantrine; Malaria, Falciparum; Molecular Epidemiology; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Recurrence; Seasons; Sesquiterpenes

One hundred and two Chinese out-patients with naturally acquired, previously untreated, falciparum malaria were selected to evaluate the efficacy of a new combination anti-malaria therapy, CGP 56697 (artemether plus benflumetol). In this open non-comparative trial each patient received a combination of 80 mg artemether and 480 mg benflumetol given orally at 0, 8, 24 and 48 hours (total: 320 mg artemether, 1,920 mg benflumetol). Patients were kept for 28 days in a transmission-free hospital in an area with chloroquine resistant falciparum malaria to prevent reinfection and to aid diagnosis of recrudescence. Progress and possible adverse effects were monitored by blood film parasitology, blood biochemistry assays, urinalysis, ECG and X-ray. Ninety-eight of the 102 patients were shown to be free of infection at 28 days, a 96.1% cure rate. Parasite reduction at 24 hours was 99.4%. Time to effect complete parasite clearance ranged from 24 to 54 hours (median 30 hours). Time for fever clearance ranged from 6 to 78 hours (median 18 hours). Recrudescence was low (3.9%). No significant adverse side-effects were encountered. It is concluded that CGP 56697, a combination anti-malaria therapy of artemether with benflumetol, offered a rapid and highly effective treatment for acute uncomplicated falciparum malaria in an area of chloroquine-resistant malaria in China.

Topics: Administration, Oral; Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; China; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Sesquiterpenes; Time Factors; Treatment Outcome

Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine.. Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters.. Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified.. Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect.

Topics: Adult; Animals; Anopheles; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Healthy Volunteers; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Sporozoites

Assessing the infectious reservoir is critical in malaria control and elimination strategies. We conducted a longitudinal epidemiological study in a high-malaria-burden region in Kenya to characterize transmission in an asymptomatic population.. 488 study participants encompassing all ages in 120 households within 30 clusters were followed for 1 year with monthly sampling. Malaria was diagnosed by microscopy and molecular methods. Transmission potential in gametocytemic participants was assessed using direct skin and/or membrane mosquito feeding assays, then treated with artemether-lumefantrine. Study variables were assessed using mixed-effects generalized linear models.. Asexual and sexual parasite data were collected from 3792 participant visits, with 903 linked with feeding assays. Univariate analysis revealed that the 6-11-year-old age group was at higher risk of harboring asexual and sexual infections than those <6 years old (odds ratio [OR] 1.68, P < .001; and OR 1.81, P < .001), respectively. Participants with submicroscopic parasitemia were at a lower risk of gametocytemia compared with microscopic parasitemia (OR 0.04, P < .001), but they transmitted at a significantly higher rate (OR 2.00, P = .002). A large proportion of the study population who were infected at least once remained infected (despite treatment) with asexual (71.7%, 291/406) or sexual (37.4%, 152/406) parasites. 88.6% (365/412) of feeding assays conducted in individuals who failed treatment the previous month resulted in transmissions.. Individuals with asymptomatic infection sustain the transmission cycle, with the 6-11-year age group serving as an important reservoir. The high rates of artemether-lumefantrine treatment failures suggest surveillance programs using molecular methods need to be expanded for accurate monitoring and evaluation of treatment outcomes.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Humans; Kenya; Malaria; Malaria, Falciparum; Parasitemia; Plasmodium falciparum

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Fluorenes; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Malaria, Falciparum; Nevirapine; Ritonavir; Uganda

Microscopic evaluation of parasite clearance is the gold standard in antimalarial drug efficacy trials. However, the presence of sub-microscopic residual parasitemia after artemisinin-based combination therapy (ACT) needs to be investigated.. One hundred and twenty (AL: n = 60, PA: n = 60) days 3 and 14 dried blood spots, negative by microscopy were analysed for residual parasitemia using nested PCR. Isolates with residual parasitemia on days 3 and 14 were further genotyped with their corresponding day-0 isolates using merozoite surface proteins msp-1, msp-2, and glurp genes for allelic similarity.. Persistent PCR-determined sub-microscopic residual parasitemia at day 3 post ACT treatment was 83.3 (AL) and 88.3% (PA), respectively (ρ = 0.600), while 63.6 and 36.4% (ρ = 0.066) isolates were parasitemic at day 14 for AL and PA, respectively. Microscopy-confirmed gametocytemia persisted from days 0 to 7 and from days 0 to 21 for AL and PA. When the alleles of day 3 versus day 0 were compared according to base pair sizes, 59% of parasites shared identical alleles for glurp, 36% each for 3D7 and FC27, while K1 was 77%, RO33 64%, and MAD20 23%, respectively. Similarly, day 14 versus day 0 was 36% (glurp), 64% (3D7), and 32% (FC27), while 73% (K1), 77% (RO33), and 41% (MAD20), respectively.. The occurrence of residual parasitemia on days 3 and 14 following AL or PA treatment may be attributable to the presence of either viable asexual, gametocytes, or dead parasite DNAs, which requires further investigation.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Humans; Malaria, Falciparum; Merozoite Surface Protein 1; Nigeria; Parasitemia; Plasmodium falciparum; Prevalence

In 2004, Ethiopia adopted artemether-lumefantrine (AL, Coartem. A 28 day onearm, prospective evaluation of the clinical and parasitological response to AL was conducted at Shecha Health Centre, Arba Minch town, Southern Ethiopia. Patients were treated with six-dose regimen of AL over three days and monitored for 28 days with clinical and laboratory assessments. Participant recruitment and outcome classification was done in accordance with the 2009 WHO methods for surveillance of anti-malarial drug efficacy guidelines.. A total of 88 study participants were enrolled and 69 of them completed the study with adequate clinical and parasitological response. Two late parasitological failures were observed, of which one was classified as a recrudescence by polymerase chain reaction (PCR). The PCRcorrected cure rate was 98.6% (95% CI 92.3-100). AL demonstrated a rapid parasite and fever clearance with no parasitaemia on day 2 and febrile cases on day 3. Gametocyte clearance was complete by day three. No serious adverse events were reported during the 28 days follow-up.. The study demonstrated high therapeutic efficacy and good safety profile of AL. This suggests the continuation of AL as the first-line drug for the treatment of uncomplicated P. falciparum malaria in Ethiopia. Periodic therapeutic efficacy studies and monitoring of markers of resistance are recommended for early detection of resistant parasites.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Ethiopia; Fever; Fluorenes; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Treatment Outcome

Return to international travel in the COVID-19 pandemic recovery period is expected to increase the number of patients with imported malaria in the United States (US). Malaria prevention in travelers and preparedness for timely diagnosis and appropriate treatment are key to minimize imported malaria morbidity and mortality. Intravenous artesunate (IVAS) is now available from commercial distributors in the US for the treatment of severe malaria. Hospitals and pharmacists should have a plan for malaria treatment, including stocking artemether-lumefantrine for uncomplicated malaria, and stocking or planning for rapid procurement of IVAS for the treatment of severe malaria.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; COVID-19; COVID-19 Testing; Early Diagnosis; Humans; Malaria; Malaria, Falciparum; Pandemics; Travel; United States

The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals.. Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population.. Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult.. Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Australia; Healthy Volunteers; Humans; Malaria, Falciparum; Parasitemia; Plasmodium falciparum

Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana.. The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Drug Tolerance; Ghana; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Plasmodium falciparum

Currently, chemotherapy stands out as the major malaria intervention strategy, however, anti-malarial resistance may hamper global elimination programs. Artemisinin-based combination therapy (ACT) stands as the drug of choice for the treatment of Plasmodium falciparum malaria. Plasmodium falciparum kelch13 gene mutations are associated with artemisinin resistance. Thus, this study was aimed at evaluating the circulation of P. falciparum k13 gene polymorphisms from Kisii County, Kenya during an era of ACT deployment.. Participants suspected to have malaria were recruited. Plasmodium falciparum was confirmed using the microscopy method. Malaria-positive patients were treated with artemether-lumefantrine (AL). Blood from participants who tested positive for parasites after day 3 was kept on filter papers. DNA was extracted using chelex-suspension method. A nested polymerase chain reaction (PCR) was conducted and the second-round products were sequenced using the Sanger method. Sequenced products were analysed using DNAsp 5.10.01 software and then blasted on the NCBI for k13 propeller gene sequence identity using the Basic Local Alignment Search Tool (BLAST). To assess the selection pressure in P. falciparum parasite population, Tajima' D statistic and Fu & Li's D test in DnaSP software 5.10.01 was used.. Out of 275 enrolled participants, 231 completed the follow-up schedule. 13 (5.6%) had parasites on day 28 hence characterized for recrudescence. Out of the 13 samples suspected of recrudescence, 5 (38%) samples were positively amplified as P. falciparum, with polymorphisms in the k13-propeller gene detected. Polymorphisms detected in this study includes R539T, N458T, R561H, N431S and A671V, respectively. The sequences have been deposited in NCBI with bio-project number PRJNA885380 and accession numbers SAMN31087434, SAMN31087433, SAMN31087432, SAMN31087431 and SAMN31087430 respectively.. WHO validated polymorphisms in the k13-propeller gene previously reported to be associated with ACT resistance were not detected in the P. falciparum isolates from Kisii County, Kenya. However, some previously reported un-validated k13 resistant single nucleotide polymorphisms were reported in this study but with limited occurrences. The study has also reported new SNPs. More studies need to be carried out in the entire country to understand the association of reported mutations if any, with ACT resistance.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Humans; Kenya; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria; Malaria, Falciparum; Treatment Failure

Intensified Malaria Control Project (IMCP) was implemented in 2005 to control malaria in all North-Eastern and Odisha states of India. The present study aimed to investigate the impact of IMCP in reducing the malaria burden in Udalguri district, Assam state of North-East India. Malaria epidemiological data were obtained for IMCP intervention (Udalguri) and nonintervention district (West Singhbhumi, Jharkhand state). IMCP activities include introducing bi-valent rapid diagnostic kits (RDTs), Artemether-Lumefantrine drug in North-East India, long-lasting insecticidal nets (LLINs) distribution, and creating awareness programs about malaria in an intensified mode. The data revealed a significant decline in annual parasite incidence (API) from 14.94 (2005) to 2.61 (2018), -37% (95%CI: -57%, -19%,

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax

Malaria continues to be a global public health problem considering the number of cases and death rate worldwide. There were no domestic cases reported from our country in the World Health Organization 2021 malaria report. All the 200-250 annual cases reported from our country have a history of travel to the endemic region. In this report, three malaria cases caused by Plasmodium falciparum and Plasmodium vivax in Kayseri province without a history of travel to the endemic region were presented. The first case was an 18-year-old male patient with no known chronic disease. He admitted to the hospital with the complaint of high fever reaching 40°C, which continued for two days, increased with chills and decreased with sweating. Physical examination revealed hepatosplenomegaly and laboratory results revealed thrombocytopenia. Species identification was made by real-time polymerase chain reaction (Rt-PCR) method in the patient with ring-shaped trophozoites in the peripheral smear. Artemether-lumefantrine and primaquine treatments were given to the patient with mixed parasitemia of P.falciparum and P.vivax. One and two days after the admission, the second and third cases also admitted with similar complaints. Mixed parasitemia was observed in all three patients who did not have a history of traveling abroad. After the antiparasitic treatment, the patients improved clinically and laboratory, and no recurrent parasitemia was observed. With the occurrence of these cases, efforts to combat vectors were initiated throughout the province. In conclusion, the presence of anopheles mosquitoes and imported cases still poses a risk for domestic malaria cases. In patients who do not have a history of traveling abroad, malaria should be considered in the clinical preliminary diagnosis and species identification should be made by methods such as Rt-PCR in order to give appropriate treatments.

Topics: Adolescent; Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Parasitemia; Travel

Even though malaria is easily preventable and treatable, it continues to have a devastating impact on people's health and livelihoods around the world. Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. This study seeks to assess the prevalence, trends and factors associated with malaria in the Shai-Osudoku District Hospital, Ghana.. A cross-sectional study was conducted to determine the prevalence, trend, and factors associated with malaria in the Shai-Osudoku District Hospital; a 10-month secondary data was extracted from February to November 2020. The extracted data were entered into Epi Data version 6 and analysed using STATA version 16. Descriptive analysis was performed to determine the prevalence, trend and socio-demographic characteristics of study participants. Simple logistic regression at a 95% confidence level was performed to investigate socio-demographic factors associated with malaria infection. Tables and charts with summary statistics were used to present the results.. Secondary data from 3896 individuals were included in the study. The age of the participants range from 0.8 to 101 years with a mean age of 32.5. The estimated prevalence of malaria during the study period is 20.9%. A majority (79.1%) of the participants who presented signs and symptoms of malaria were negative after testing. The prevalence of malaria cases increased progressively from 6.7 to 55.4% across the ten months. The simple logistic regression at a 95% confidence level revealed that age group, sex, residential status, religion, occupation and marital status were statistically significantly associated with malaria. The results shows that persons who tested positive for malaria were mostly treated with artemether-lumefantrine (46.1%), some malaria positive cases were given artesunate injection (11.6%), dihydroartemisinin-piperaquine (16.2%) and oral artemether-lumefantrine (6.5%). Surprisingly 19.6% of the malaria-positive cases were not given any form of malaria medication.. Factors found to influence malaria infection in the Shai-Osudoku District Hospital include participant's age, sex, residential status, religious affiliation occupation and marital status. The findings of this study showed that malaria remains a serious public health problem in the Shai Osudoku District Hospital. The information obtained from this study can guide the implementation of malaria prevention, control and elimination strategies in Ghana.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Cross-Sectional Studies; Ghana; Hospitals, District; Humans; Infant; Malaria; Malaria, Falciparum; Middle Aged; Prevalence; Young Adult

Prior to 2018, malaria therapeutic efficacy studies (TESs) in Nigeria were implemented separately at different sites, as assigned by the National Malaria Elimination Program (NMEP). In 2018, however, the NMEP engaged the Nigerian Institute of Medical Research to coordinate the 2018 TESs in 3 of 14 sentinel sites with the objective of standardizing their conduct across all three sites: Enugu, Kano, and Plateau states in three of six geopolitical zones. Artemether-lumefantrine and artesunate-amodiaquine, the two first-line drugs for treatment of acute uncomplicated malaria in Nigeria, were tested in both Kano and Plateau states. In Enugu State, however, artemether-lumefantrine and dihydroartemisinin-piperaquine were the test drugs, with dihydroartemisinin-piperaquine being tested for potential inclusion in Nigerian treatment policy. The TES was conducted in 6-month to 8-year-old children and was funded by the Global Fund with additional support from the WHO. A multipartite core team comprised of the NMEP, the WHO, the U.S. Presidential Malaria Initiative, academia, and the Nigerian Institute of Medical Research was set up to oversee the execution of the 2018 TES. This communication reports best practices adopted to guide its coordination, and lessons learned during in the process, including applying developed standard operating procedures, powering the sample size adequately for each site to report independently, training the investigating team for fieldwork, facilitating stratification of decisions, determining efficiencies derived from monitoring and quality assessment, and optimizing logistics. The planning and coordination of the 2018 TES activities is a model of a consultative process for the sustainability of antimalarial resistance surveillance in Nigeria.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria; Malaria, Falciparum; Nigeria

Artemisinin-based combination therapy (ACT) is the most effective treatment for malaria, and has significantly reduced morbimortality. Polymorphisms associated with the Plasmodium falciparum Kelch gene (Pfkelch13) have been associated with delayed parasite clearance even with ACT treatment.. The Pfkelch13 gene was sequenced from P. falciparum infected patients (n = 159) with uncomplicated malaria in Niger. An adequate clinical and parasitological response (ACPR) was reported in 155 patients. Four (n = 4) patients had treatment failure (TF) that were not reinfections-two of which had late parasitological failures (LPF) and two had late clinical failures (LCF).. Thirteen single nucleotide polymorphisms (SNPs) were identified of which seven were non-synonymous (C469R, T508S, R515T, A578S, I465V, I437V, F506L,), and three were synonymous (P443P, P715P, L514L). Three SNP (C469R, F506L, P715P) were present before ACT treatment, while seven mutations (C469R, T508S, R515T, L514L, P443P, I437V, I465V) were selected by artemether/lumefantrine (AL)-five of which were non-synonymous (C469R, T508S, R515T, I437V, I465V). Artesunate/amodiaquine (ASAQ) has selected any mutation. One sample presented three cumulatively non-synonymous SNPs-C469R, T508S, R515T.. This study demonstrates intra-host selection of Pfkelch13 gene by AL. The study highlights the importance of LCF and LPF parasites in the selection of resistance to ACT. Further studies using gene editing are required to confirm the potential implication of resistance to ACT with the most common R515T and T508S mutations. It would also be important to elucidate the role of cumulative mutations.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Humans; Malaria, Falciparum; Niger; Plasmodium falciparum; Polymorphism, Single Nucleotide; Treatment Failure

Malaria remains a public health concern globally. Resistance to anti-malarial drugs has consistently threatened the gains in controlling the malaria parasites. Currently, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the treatment regimens against Plasmodium falciparum infections in many African countries, including Kenya. Recurrent infections have been reported in patients treated with AL or DP, suggesting the possibility of reinfection or parasite recrudescence associated with the development of resistance against the two therapies. The Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) K65 selection marker has previously been associated with decreased lumefantrine susceptibility. This study evaluated the frequency of the Pfnfs1 K65 resistance marker and associated K65Q resistant allele in recurrent infections collected from P. falciparum-infected individuals living in Matayos, Busia County, in western Kenya.. Archived dried blood spots (DBS) of patients with recurrent malaria infection on clinical follow-up days after treatment with either AL or DP were used in the study. After extraction of genomic DNA, PCR amplification and sequencing analysis were employed to determine the frequencies of the Pfnfs1 K65 resistance marker and K65Q mutant allele in the recurrent infections. Plasmodium falciparum msp1 and P. falciparum msp2 genetic markers were used to distinguish recrudescent infections from new infections.. The K65 wild-type allele was detected at a frequency of 41% while the K65Q mutant allele was detected at a frequency of 22% in the recurrent samples. 58% of the samples containing the K65 wild-type allele were AL treated samples and while 42% were DP treated samples. 79% of the samples with the K65Q mutation were AL treated samples and 21% were DP treated samples. The K65 wild-type allele was detected in three recrudescent infections (100%) identified from the AL treated samples. The K65 wild-type allele was detected in two recrudescent DP treated samples (67%) while the K65Q mutant allele was identified in one DP treated (33%) recrudescent sample.. The data demonstrate a higher frequency of the K65 resistance marker in patients with recurrent infection during the study period. The study underscores the need for consistent monitoring of molecular markers of resistance in regions of high malaria transmission.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Humans; Kenya; Lumefantrine; Malaria; Malaria, Falciparum; Mutation; Plasmodium falciparum; Prevalence; Quinolines; Reinfection

Substandard anti-malarial agents pose a significant challenge to effective malaria control and elimination efforts especially in sub-Saharan Africa. The quality of anti-malarials in most low-and-middle income countries (LMICs) is affected by several factors including inadequate regulation and limited resources. In this study, the pharmacopeial quality of artemether-lumefantrine (AL) in low and high malaria transmission settings in Uganda was assessed.. This was a cross-sectional study conducted among randomly selected private drug outlets. The AL anti-malarials available in drug outlets were purchased using overt method. The samples were screened for quality using visual inspection, weight uniformity, content assay and dissolution tests. The assay test was done using liquid chromatography-mass spectrometry (LC-MS). The samples were considered substandard if the active pharmaceutical ingredient (API) content was outside 90-110% range of the label claim. Dissolution test was conducted following United States Pharmacopoeia (USP) method. Data was analysed using descriptive statistics and presented as means with standard deviations, frequencies, and proportions. Correlation between medicine quality and independent variables was determined using Fisher's exact test of independence at 95% level of significance.. A total of 74 AL anti-malarial samples were purchased from high (49/74; 66.2%) and low (25/74; 33.8%) malaria transmission settings. The most common batch of AL was LONART, 32.4% (24/74), with 33.8% (25/74) being 'Green leaf'. Overall prevalence of substandard quality artemether-lumefantrine was 18.9% (14/74; 95% CI: 11.4-29.7). Substandard quality AL was significantly associated with setting (p = 0.002). A total of 10 samples (13.5%) failed artemether content assay test while, 4 samples (5.4%, 4/74) failed the lumefantrine assay test. One sample from a high malaria transmission setting failed both artemether and lumefantrine assay content test. Of the samples that failed artemether assay test, 90% had low (< 90%) artemether content. All the samples passed visual inspection and dissolution tests.. Artemether-lumefantrine agents, the recommended first-line treatment for uncomplicated malaria with APIs outside the recommended pharmacopeial content assay limit is common especially in high malaria transmission settings. There is need for continuous surveillance and monitoring of the quality of artemisinin-based anti-malarials across the country by the drug regulatory agency.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cross-Sectional Studies; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Uganda

Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether-lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission.. 230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant.. Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y-Y184F-D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05).. Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y-Y184F-D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Chloroquine; Drug Resistance; Ethiopia; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins

Like most countries in sub-Saharan African countries, Benin continues to bear a heavy malaria burden. In 2014, the National Malaria Control Programme (NMCP) changed its treatment policy, and recommended the use of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated Plasmodium falciparum cases. The study presented here was conducted to investigate the impact of current antimalarial drug resistance on the country. Molecular surveillance targeting the Pfcrt, Pfmdr1, Pfkelch13, dhfr, and dhps genes was carried out on samples from patients positive for P. falciparum malaria by microscopy, LAMP and PCR diagnostic test. Molecular analysis was performed using targeted amplicon deep sequencing (TADS). In addition, the frequency of parasites with dual deletion of the histidine-rich protein 2 and 3 genes (pfhrp2 and pfhrp3), known to be responsible of the performance of HRP-based malaria rapid diagnostic tests (HRP-RDT), was estimated. Fifty-three falciparum samples collected at the Saint Jean de Dieu hospital in Tanguiéta, Benin, were tested. No Pfkelch13 validated or candidate artemisinin partial resistant variants were identified. A marked prevalence of Asn51Ile (N51I), Cys59Arg (C59R), and Ser108Asn (S108N) mutant alleles was found in the dhfr gene, representing the most frequent genotype (64%). Five-point mutations were detected in dhps, Ile431Val (I431V), Ser436Ala (S436A), Ala437Gly (A437G), Ala581Gly (A581G), Ala613Ser (A613S) of which the third was the most common (92%). No mutation was identified in dhps Lys540Glu (K540E). The quintuple mutant genotype resulting from the combination of the dhfr triple mutant (51I/59R/108N) with the dhps double mutant 436A/437G was detected at a frequency of 30%. Low levels of mutations in Pfcrt and no mutation at codon 86 in the Pfmdr1 DNA fragment were observed, whereas a high level of Tyr184Phe (Y184F) polymorphism in the Pfmdr1 gene was found. These results could be indicative, over a decade after the implementation of ACT therapy, of the return of chloroquine-sensitive but artemether-lumefantrine resistant falciparum genotypes in Benin. There was no evidence of HRP2 and HRP3 deletions. Data from the present study support the need for routine monitoring of molecular markers of antimalarial drug resistance as part of surveillance activities aimed to make informed treatment policy decisions at the national level.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Benin; Drug Combinations; Drug Resistance; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase

This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations.. This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia).. Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died.. The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Prescriptions; Prospective Studies; Tanzania; World Health Organization

Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).. A single-arm prospective study assessing the efficacy of AS-AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS-AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes.. By the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2-100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates.. The results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance. Trial registration ACTRN12622001476729.

Topics: Adult; Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Chad; Female; Humans; Malaria, Falciparum; Pregnancy; Prospective Studies

Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether-lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81-92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Mutation; Plasmodium falciparum; Rwanda

Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in. In this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent. We noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the. The emergence and spread of

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Eritrea; Humans; Malaria, Falciparum; Plasmodium falciparum; Prevalence

Artemether-lumefantrine is an artemisinin-based combination therapy for the treatment of malaria, which are primarily metabolized by cytochrome P450 3A4. Therapeutic difference caused by gene polymorphisms of CYP3A4 may lead to uncertain adverse side effects or treatment failure. The aim of this study was to evaluate the effect of CYP3A4 gene polymorphism on artemether-lumefantrine metabolism in vitro. Enzyme kinetics assay was performed using recombinant human CYP3A4 cell microsomes. The analytes, dihydroartimisinin and desbutyl-lumefantrine, were detected by ultra-performance liquid chromatography tandem mass spectrometry. The results demonstrated that compared to CYP3A4.1, the intrinsic clearance of CYP3A4.4, 5, 9, 16, 18, 23, 24, 28, 31-34 significantly reduced for artemether (58.5%-93.3%), and CYP3A4.17 almost loss catalytic activity. Simultaneously, CYP3A4.5, 14, 17, 24 for lumefantrine were decreased by 56.1%-99.6%, and CYP3A4.11, 15, 18, 19, 23, 28, 29, 31-34 for lumefantrine was increased by 51.7%-296%. The variation in clearance rate indicated by molecular docking could be attributed to the disparity in the binding affinity of artemether and lumefantrine with CYP3A4. The data presented here have enriched our understanding of the effect of CYP3A4 gene polymorphism on artemether-lumefantrine metabolizing. These findings serve as a valuable reference and provide insights for guiding the treatment strategy involving artemether-lumefantrine.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cytochrome P-450 CYP3A; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Molecular Docking Simulation

Polymorphonuclear neutrophils (PMN) are involved in pathogen clearance by phagocytosis. However, the role of PMNs in the efficacy of artemisinin-based combination therapy (ACT) is poorly understood.. In a prospective longitudinal in vivo study, neutrophil rates were compared with malaria carriage after treatment with different ACTs: Artemether - lumefantrine (AL), Artesunate - amodiaquine (ASAQ), Dihydroartemisinin - piperaquine (DP) or Pyronaridine artesunate (PA). The study cases were classified as having neutropenia, normal neutrophil levels or neutrophilia depending on the level of neutrophils in the blood. This study included 3148 patients and was analyzed using R.. On day 7, only four patients in the neutropenia group and treated with AL had a malaria positive blood smear based on microscopy. On day 28, the rate of recurrent parasitemia in the AL arm was significantly higher in neutropenia patients (50.9%) than in patients with normal rates of neutrophils (43.1%) or in those with neutrophilia (6.0%) (p < 0.001). In ASAQ arm, the rate of recurrent Plasmodium falciparum parasitemia was 58.8% in the neutropenia group versus 29.4% in patients with normal rates of neutrophils and 11.8% in patients with neutrophilia (p < 0.001). No patient treated with DP with normal neutrophil counts or neutrophilia was carrying malaria parasites on day 28. Among the 15 patients with parasitemia on day 28 in the PA arm, 11 (73.33%) had neutropenia while 4 (26.67%) had a normal neutrophil count (p < 0.001).. Patients with neutropenia had higher rates of recurrent P. falciparum parasitemia after ACT.

Topics: Africa; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Drug Combinations; Ethanolamines; Humans; Malaria; Malaria, Falciparum; Neutropenia; Neutrophils; Parasitemia; Plasmodium falciparum; Prospective Studies

Attractive targeted sugar bait (ATSB) is a novel approach to vector control, offering an alternative mode of insecticide delivery via the insect alimentary canal, with potential to deliver a variety of compounds new to medical entomology and malaria control. Its potential to control mosquitoes was recently demonstrated in major field trials in Africa. The pyrrole chlorfenapyr is an insecticide new to malaria vector control, and through its unique mode of action-disruption of ATP mediated energy transfer in mitochondria-it may have direct action on energy transfer in the flight muscle cells of mosquitoes. It may also have potential to disrupt mitochondrial function in malarial parasites co-existing within the infected mosquito. However, little is known about the impact of such compounds on vector competence in mosquitoes responsible for malaria transmission.. In this study, ATSBs containing chlorfenapyr insecticide and, as a positive control, the anti-malarial drugs artemether/lumefantrine (A/L) were compared for their effect on Plasmodium falciparum development in wild pyrethroid-resistant Anopheles gambiae sensu stricto (s.s.) and for their capacity to reduce vector competence. Female mosquitoes were exposed to ATSB containing either sublethal dose of chlorfenapyr (CFP: 0.025%) or concentrations of A/L ranging from 0.4/2.4 mg/ml to 2.4/14.4 mg/ml, either shortly before or after taking infective blood meals. The impact of their component compounds on the prevalence and intensity of P. falciparum infection were compared between treatments.. These results are evidence that chlorfenapyr, in addition to its direct killing effect on the vector, has the capacity to block Plasmodium transmission by interfering with oocyte development inside pyrethroid-resistant mosquitoes, and through this dual action may potentiate its impact under field conditions.

Topics: Animals; Anopheles; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Carbohydrates; Female; Humans; Insecticide Resistance; Insecticides; Malaria; Malaria, Falciparum; Male; Mosquito Control; Mosquito Vectors; Plasmodium falciparum; Pyrethrins; Sugars

Studies have proposed that malaria may lead to electrocardiographic (ECG) changes and pericardial inflammation. We aimed to investigate the frequency of ECG alterations, determined by ECG and Holter monitoring, and pericardial effusion in patients with malaria infection. We performed a prospective observational study of adult patients with uncomplicated malaria in Amazonas, Brazil. Peripheral blood smears, ECG, and bedside echocardiography were conducted before antimalarial treatment and repeated at follow-up after completed treatment. We evaluated the diagnostic value of PR-segment depression, PR-segment elevation, and Spodick's sign for detecting pericardial effusion. A subset of patients underwent Holter monitoring at baseline. Among 98 cases of uncomplicated malaria (55% men; mean age 40 years; median parasite density 1,774/µl), 75 had Plasmodium vivax, 22 Plasmodium falciparum, and 1 had mixed infection. At baseline, 17% (n = 17) had PR-segment depression, 12% (n = 12) PR-segment elevation, 3% (n = 2) Spodick's sign, and the prevalence of pericardial effusion was 9% (n = 9). ECG alterations had sensitivities of 22% to 89% and specificities of 88% to 100% for detecting pericardial effusion at baseline. PR-segment depression had the best accuracy (sensitivity 89%, specificity 90%). Of the 25 patients, 4 patients who did not have pericardial effusion, displayed nonsustained ventricular tachycardia, determined by Holter monitoring (median duration 43 hours). Follow-up examination data were obtained for 71 patients (median 31 days), for whom PR-segment depression, elevation, and pericardial effusion had reduced significantly (p <0.05). In conclusion, our findings suggest that ECG alterations may be useful to detect pericardial effusion in malaria and that these findings decrease after completed antimalarial treatment.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Brazil; Case-Control Studies; Chloroquine; Electrocardiography; Electrocardiography, Ambulatory; Female; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Pericardial Effusion; Primaquine; Prospective Studies; Sensitivity and Specificity; Tachycardia, Ventricular

In areas highly endemic for malaria, Plasmodium falciparum infection prevalence peaks in school-age children, adversely affecting health and education. School-based intermittent preventive treatment reduces this burden but concerns about cost and widespread use of antimalarial drugs limit enthusiasm for this approach. School-based screening and treatment is an attractive alternative. In a prospective cohort study, we evaluated the impact of school-based screening and treatment on the prevalence of P. falciparum infection and anemia in 2 transmission settings.. We screened 704 students in 4 Malawian primary schools for P. falciparum infection using rapid diagnostic tests (RDTs), and treated students who tested positive with artemether-lumefantrine. We determined P. falciparum infection by microscopy and quantitative polymerase chain reaction (qPCR), and hemoglobin concentrations over 6 weeks in all students.. Prevalence of infection by RDT screening was 37% (9%-64% among schools). An additional 9% of students had infections detected by qPCR. Following the intervention, significant reductions in infections were detected by microscopy (adjusted relative reduction [aRR], 48.8%; P < .0001) and qPCR (aRR, 24.5%; P < .0001), and in anemia prevalence (aRR, 30.8%; P = .003). Intervention impact was reduced by infections not detected by RDT and new infections following treatment.. School-based screening and treatment reduced P. falciparum infection and anemia. This approach could be enhanced by repeating screening, using more-sensitive screening tests, and providing longer-acting drugs.. NCT04858087.

Topics: Anemia; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Humans; Malaria; Malaria, Falciparum; Malawi; Plasmodium falciparum; Prevalence; Prospective Studies; Schools

We described a case of Plasmodium malariae malaria in a traveler returning from the Democratic Republic of Congo to Belgium. This occurred despite successful artemether-lumefantrine treatment for Plasmodium falciparum three weeks earlier and in the absence of re-exposure in an endemic area. We discuss possible explanations for this unusual observation.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Fluorenes; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Plasmodium malariae

Accurate malaria diagnosis and appropriate treatment at local health facilities are critical to reducing morbidity and human reservoir of infectious gametocytes. The current study assessed the accuracy of malaria diagnosis and treatment practices in three health care facilities in rural western Kenya.. The accuracy of malaria detection and treatment recommended compliance was monitored in two public and one private hospital from November 2019 through March 2020. Blood smears from febrile patients were examined by hospital laboratory technicians and re-examined by an expert microscopists thereafter subjected to real-time polymerase chain reaction (RT-PCR) for quality assurance. In addition, blood smears from patients diagnosed with malaria rapid diagnostic tests (RDT) and presumptively treated with anti-malarial were re-examined by an expert microscopist.. A total of 1131 febrile outpatients were assessed for slide positivity (936), RDT (126) and presumptive diagnosis (69). The overall positivity rate for Plasmodium falciparum was 28% (257/936). The odds of slide positivity was higher in public hospitals, 30% (186/624, OR:1.44, 95% CI = 1.05-1.98, p < 0.05) than the private hospital 23% (71/312, OR:0.69, 95% CI = 0.51-0.95, p < 0.05). Anti-malarial treatment was dispensed more at public hospitals (95.2%, 177/186) than the private hospital (78.9%, 56/71, p < 0.0001). Inappropriate anti-malarial treatment, i.e. artemether-lumefantrine given to blood smear negative patients was higher at public hospitals (14.6%, 64/438) than the private hospital (7.1%, 17/241) (p = 0.004). RDT was the most sensitive (73.8%, 95% CI = 39.5-57.4) and specific (89.2%, 95% CI = 78.5-95.2) followed by hospital microscopy (sensitivity 47.6%, 95% CI = 38.2-57.1) and specificity (86.7%, 95% CI = 80.8-91.0). Presumptive diagnosis had the lowest sensitivity (25.7%, 95% CI = 13.1-43.6) and specificity (75.0%, 95% CI = 50.6-90.4). RDT had the highest non-treatment of negatives [98.3% (57/58)] while hospital microscopy had the lowest [77.3% (116/150)]. Health facilities misdiagnosis was at 27.9% (77/276). PCR confirmed 5.2% (4/23) of the 77 misdiagnosed cases as false positive and 68.5% (37/54) as false negative.. The disparity in malaria diagnosis at health facilities with many slide positives reported as negatives and high presumptive treatment of slide negative cases, necessitates augmenting microscopic with RDTs and calls for Ministry of Health strengthening supportive infrastructure to be in compliance with treatment guidelines of Test, Treat, and Track to improve malaria case management.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Diagnostic Tests, Routine; Fever; Health Personnel; Humans; Kenya; Malaria; Malaria, Falciparum; Real-Time Polymerase Chain Reaction; Rural Population; Sensitivity and Specificity

Artesunate-amodiaquine (ASAQ) and Artemether-lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate-amodiaquine and Artemether-lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated.. The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/ ). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples.. Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6-96.7%) in Bensonville and 92.7% (95% CI: 83.4.8-96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357).. This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy. Trial registration ACTRN12617001064392.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Child; Chloroquine; DNA Copy Number Variations; Female; Humans; Liberia; Malaria; Malaria, Falciparum; Membrane Transport Proteins; Plasmodium falciparum; Pregnancy

In Uganda, Artemether-Lumefantrine and Artesunate are recommended for uncomplicated and severe malaria respectively, but are currently threatened by parasite resistance. Genetic and epigenetic factors play a role in predisposing Plasmodium falciparum parasites to acquiring Pfkelch13 (K13) mutations associated with delayed artemisinin parasite clearance as reported in Southeast Asia. In this study, we report on the prevalence of mutations in the K13, pfmdr-2 (P. falciparum multidrug resistance protein 2), fd (ferredoxin), pfcrt (P. falciparum chloroquine resistance transporter), and arps10 (apicoplast ribosomal protein S10) genes in Plasmodium falciparum parasites prior to (2005) and after (2013) introduction of artemisinin combination therapies for malaria treatment in Uganda. A total of 200 P. falciparum parasite DNA samples were screened. Parasite DNA was extracted using QIAamp DNA mini kit (Qiagen, GmbH, Germany) procedure. The PCR products were sequenced using Sanger dideoxy sequencing method. Of the 200 P. falciparum DNA samples screened, sequencing for mutations in K13, pfmdr-2, fd, pfcrt, arps10 genes was successful in 142, 186, 141, 128 and 74 samples respectively. Overall, we detected six (4.2%, 6/142; 95%CI: 1.4-7.0) K13 single nucleotide polymorphisms (SNPs), of which 3.9% (2/51), 4.4% (4/91) occurred in 2005 and 2013 samples respectively. All four K13 SNPs in 2013 samples were non-synonymous (A578S, E596V, S600C and E643K) while of the two SNPs in 2005 samples, one (Y588N) is non-synonymous and the other (I587I) is synonymous. There was no statistically significant difference in the prevalence of K13 (p = 0.112) SNPs in the samples collected in 2005 and 2013. The overall prevalence of SNPs in pfmdr-2 gene was 39.8% (74/186, 95%CI: 25.1-50.4). Of this, 4.2% (4/95), 76.9% (70/91) occurred in 2005 and 2013 samples respectively. In 2005 samples only one SNP, Y423F (4.2%, 4/95) was found while in 2013, Y423F (38.5%, 35/91) and I492V (38.5%, 35/91) SNPs in the pfmdr-2 gene were found. There was a statistically significant difference in the prevalence of pfmdr-2 SNPs in the samples collected in 2005 and 2013 (p<0.001). The overall prevalence of arps10 mutations was 2.7% (2/72, 95%CI: 0.3-4.2). Two mutations, V127M (4.5%: 1/22) and D128H (4.5%: 1/22) in the arps10 gene were each found in P. falciparum parasite samples collected in 2013. There was no statistically significant difference in the prevalence of arps10 SNPs in the samples collected in 2005

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Malaria; Malaria, Falciparum; Mutation; Parasites; Plasmodium falciparum; Prevalence; Protozoan Proteins; Uganda

Topics: Anemia, Sickle Cell; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Ethanolamines; Fluorenes; Genotype; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Tanzania

The development of resistance by Plasmodium falciparum to anti-malarial drugs impedes any benefits of the drug. In addition, absence or delayed availability of current anti-malarial drugs in remote areas has the potential to results to parasite escape and continuous transmission.. The case of a 29-year old pregnant woman from Biase Local Government Area in Cross River State Nigeria presenting with febrile illness and high body temperature of 38.7 °C was reported. She looked pale and vomited twice on arrival at the health facility. Her blood smear on the first day of hospitalization was positive for P. falciparum by RDT, microscopy (21,960 parasite/µl) and real-time PCR, with a PCV of 18%. She was treated with 600 mg intravenous quinine in 500 ml of 5% Dextrose/0.9% Saline 8-hourly for 24 h. On the second day of hospitalization, she complained of weakness, persistent high-grade fever and vaginal bleeding. A bulging amnion from an extended cervix was observed. Following venous blood collection for laboratory investigations, 600 µg of misoprostol was inserted into the posterior fornix of her vagina as part of her obstetric care. Parenteral quinine was discontinued, and she was given full therapeutic regimen of artemether-lumefantrine 80/480 mg tablets to be taken for 3 days beginning from the second day. Her blood samples on the second and third day of hospitalization remained positive for P. falciparum by all three diagnostic methods. Single nucleotide polymorphism (SNP) assay on all three P. falciparum isolates revealed the presence of variants associated with multiple drug resistant markers.. Infecting P. falciparum isolates may have been resistant to initial quinine treatment resulting from parasite cross-resistance with other quinoline associated resistant markers such as 86Y and 184 F.. Therefore, the likely transmission of similarly resistant parasites in the study area calls for reinforcement of interventions and adherence to current World Health Organization guidelines in administering only approved drugs to individuals in order to mitigate parasite escape and eventual transmission to other susceptible individuals.

Topics: Abortion, Spontaneous; Adult; Africa, Western; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Resistance; Drug Resistance, Multiple; Female; Humans; Malaria; Malaria, Falciparum; Nigeria; Plasmodium falciparum; Pregnancy; Pregnant Women; Quinine

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Clindamycin; Drug Combinations; Ethanolamines; Fluorenes; Humans; Kenya; Malaria, Falciparum; Quinine

In Burkina Faso, malaria remains the first cause of medical consultation and hospitalization in health centres. First-line case management of malaria in the country's health facilities is based on the use of artemisinin-based combination therapy (ACT). To optimize the use of these anti-malarial drugs in the perspective of mitigating the emergence of artemisinin resistance, which is a serious threat to malaria control and elimination, a pilot programme using multiple first-line therapies (MFTs) [three artemisinin-based combinations-pyronaridine-artesunate, dihydroartemisinin-piperaquine and artemether-lumefantrine] has been designed for implementation. As the success of this MFT pilot programme depends on the perceptions of key stakeholders in the health system and community members, the study aimed to assess their perceptions on the implementation of this strategy.. Semi-structured interviews, including 27 individual in-depth interviews and 41 focus groups discussions, were conducted with key stakeholders including malaria control policymakers and implementers, health system managers, health workers and community members. Volunteers from targets stakeholder groups were randomly selected. All interviews were recorded, transcribed and translated. Content analysis was performed using the qualitative software programme QDA Miner.. The interviews revealed a positive perception of stakeholders on the implementation of the planned MFT programme. They saw the strategy as an opportunity to strengthen the supply of anti-malarial drugs and improve the management of fever and malaria. However, due to lack of experience with the products, health workers and care givers expressed some reservations about the effectiveness and side-effect profiles of the two anti-malarial drugs included as first-line therapy in the MFT programme (pyronaridine-artesunate, dihydroartemisinin-piperaquine). Questions were raised about the appropriateness of segmenting the population into three groups and assigning a specific drug to each group.. The adherence of both populations and key stakeholders to the MFT implementation strategy will likely depend on the efficacy of the proposed drugs, the absence of, or low frequency of, side-effects, the cost of drugs and availability of the different combinations.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Burkina Faso; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Malaria, Falciparum; Naphthyridines

Artemether/lumefantrine is the most commonly used artemisinin-based combination treatment (ACT) for malaria in sub-Saharan Africa. Drug resistance to ACT components is a major threat to malaria elimination efforts. Therefore, rigorous monitoring of drug efficacy is required for adequate management of malaria and to sustain the effectiveness of ACTs.. This study identified and described genomic loci that correlate with differences in ex vivo responses of natural Plasmodium falciparum isolates from The Gambia to antimalarial drugs.. Natural P. falciparum isolates from The Gambia were assayed for IC50 responses to four antimalarial drugs (artemether, dihydroartemisinin, amodiaquine and lumefantrine). Genome-wide SNPs from 56 of these P. falciparum isolates were applied to mixed-model regression and network analyses to determine linked loci correlating with drug responses. Genomic regions of shared haplotypes and positive selection within and between Gambian and Cambodian P. falciparum isolates were mapped by identity-by-descent (IBD) analysis of 209 genomes.. SNPs in 71 genes, mostly involved in stress and drug resistance mechanisms correlated with drug responses. Additionally, erythrocyte invasion and permeability loci, including merozoite surface proteins (Pfdblmsp, Pfsurfin), and high-molecular-weight rhoptry protein 2 (Pfrhops2) were correlated with responses to multiple drugs. Haplotypes of pfdblmsp2 and known drug resistance loci (pfaat1, pfcrt and pfdhfr) from The Gambia showed high IBD with those from Cambodia, indicating co-ancestry, with significant linkage disequilibrium between their alleles.. Multiple linked genic loci correlating with drug response phenotypes suggest a genomic backbone may be under selection by antimalarials. This calls for further analysis of molecular pathways to drug resistance in African P. falciparum.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Resistance; Gambia; Ligands; Lumefantrine; Malaria; Malaria, Falciparum; Merozoites; Plasmodium falciparum; Protozoan Proteins

Artemisinin-resistant genotypes of Plasmodium falciparum have now emerged a minimum of six times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy. We aimed to model and evaluate the long-term effects of high levels of partner-drug resistance on the early emergence of artemisinin-resistant genotypes.. Using a consensus modelling approach, we used three individual-based mathematical models of Plasmodium falciparum transmission to evaluate the effects of pre-existing partner-drug resistance and ACT deployment on the evolution of artemisinin resistance. Each model simulates 100 000 individuals in a particular transmission setting (malaria prevalence of 1%, 5%, 10%, or 20%) with a daily time step that updates individuals' infection status, treatment status, immunity, genotype-specific parasite densities, and clinical state. We modelled varying access to antimalarial drugs if febrile (coverage of 20%, 40%, or 60%) with one primary ACT used as first-line therapy: dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (ASAQ), or artemether-lumefantrine (AL). The primary outcome was time until 0·25 580Y allele frequency for artemisinin resistance (the establishment time).. Higher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all models, a 10-fold increase in the frequency of partner-drug resistance genotypes on average corresponded to loss of artemisinin efficacy 2-12 years earlier. Most reductions in time to artemisinin resistance establishment were observed after an increase in frequency of the partner-drug resistance genotype from 0·0 to 0·10.. Partner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher-grade partner-drug resistance has the largest effect, with piperaquine resistance accelerating the early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.. Schmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Consensus; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum

Topics: Adolescent; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Disease Progression; Ethanolamines; Ethiopia; Fluorenes; Humans; Malaria; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Sudan; Treatment Outcome

Antimalarial resistance threatens global malaria control efforts. The World Health Organization (WHO) recommends routine antimalarial efficacy monitoring through a standardized therapeutic efficacy study (TES) protocol. From June 2016 to March 2017, children with uncomplicated P. falciparum mono-infection in Siaya County, Kenya were enrolled into a standardized TES and randomized (1:1 ratio) to a 3-day course of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP). Efficacy outcomes were measured at 28 and 42 days. A total of 340 children were enrolled. All but one child cleared parasites by day 3. PCR-corrected adequate clinical and parasitological response (ACPR) was 88.5% (95% CI: 80.9 to 93.3%) at day 28 for AL and 93.0% (95% CI: 86.9 to 96.4%) at day 42 for DP. There were 9.6 times (95% CI: 3.4 to 27.2) more reinfections in the AL arm compared to the DP arm at day 28, and 3.1 times (95% CI: 1.9 to 4.9) more reinfections at day 42. Both AL and DP were efficacious (per WHO 90% cutoff in the confidence interval) and well tolerated for the treatment of uncomplicated malaria in western Kenya, but AL efficacy appears to be waning. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Folic Acid Antagonists; Humans; Infant; Kenya; Malaria; Malaria, Falciparum; Piperazines; Plasmodium falciparum; Quinolines; Reinfection

Therapeutic efficacy of artemether-lumefantrine is highly dependent on adequate systemic exposure to the partner drug lumefantrine particularly day 7 lumefantrine plasma concentration. There has been contradicting findings on the role of the cut-off values in predicting treatment outcomes among malaria patients in malaria endemic regions. This study assesses the day 3 and 7 lumefantrine plasma concentrations including related determinant factors and their influence on treatment outcomes among treated Tanzanian children and adults in uncontrolled conditions (real life condition).. Data was nested from an efficacy study employing the WHO protocol, 2015 for monitoring antimalarial drug efficacy. Lumefantrine plasma concentration was measured by high performance liquid chromatography with ultraviolet (HPLC-UV).. Lumefantrine plasma concentrations below 175ng/ml and 200ng/ml on day 3 and 7 did not affect adequate clinical and parasitological response (ACPR) and recurrence of infection (p = 0.428 and 0.239 respectively). Age and baseline parasitemia were not associated to day 3 median lumefantrine plasma concentrations (p = 0.08 and 0.31 respectively) and day 7 lumefantrine plasma concentrations (p = 0.07 and 0.41 respectively). However, the day 3 and day 7 lumefantrine plasma concentrations were significantly higher in males compared to females (p = 0.03 and 0.042 respectively).. Lumefantrine plasma concentrations below cut-off points (175ng/ml and 200ng/ml) on day 3 and 7 did not influence treatment outcomes.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Tanzania; Treatment Outcome

Plasmodium falciparum resistance to series of anti-malarial drugs is a major challenge in efforts to control and/or eliminate malaria globally. In 1998, following the widespread of chloroquine (CQ) resistant P. falciparum, Ethiopia switched from CQ to sulfadoxine-pyrimethamine (SP) and subsequently in 2004 from SP to artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria. Data on the prevalence of CQ resistance markers after more than two decades of its removal is important to map the selection pressure behind the targets codons of interest. The present study was conducted to determine the prevalence of mutations in Pfcrt K76T and Pfmdr1 N86Y codons among malaria-infected patients from Adama, Olenchiti and Metehara sites of East Shewa zone, Oromia Regional State, Ethiopia.. Finger-prick whole blood samples were collected on 3MM Whatman ® filter papers from a total of 121 microscopically confirmed P. falciparum infected patients. Extraction of parasite DNA was done by Chelex-100 method from dried blood spot (DBS). Genomic DNA template was used to amplify Pfcrt K76T and Pfmdr1 N86Y codons by nested PCR. Nested PCR products were subjected to Artherobacter protophormiae-I (APoI) restriction enzyme digestion to determine mutations at codons 76 and 86 of Pfcrt and Pfmdr1 genes, respectively.. Of 83 P. falciparum isolates successfully genotyped for Pfcrt K76T, 91.6% carried the mutant genotypes (76T). The prevalence of Pfcrt 76T was 95.7%, 92.5% and 84.5% in Adama, Metehara and Olenchiti, respectively. The prevalence of Pfcrt 76T mutations in three of the study sites showed no statistical significance difference (χ. Although CQ officially has been ceased for the treatment of falciparum malaria for more than two decades in Ethiopia, greater proportions of P. falciparum clinical isolates circulating in the study areas carry the mutant 76T genotypes indicating the presence of indirect CQ pressure in the country. However, the return of Pfmdr1 N86 wild-type allele may be favoured by the use of AL for the treatment of uncomplicated falciparum malaria.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Chloroquine; Drug Resistance; Ethiopia; Genotype; Health Facilities; Humans; Malaria; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Prevalence; Protozoan Proteins

Impacts of nationally directed malaria control interventions hinge on understanding malaria transmission and prevention at the community level. The decision to seek care or health-seeking behaviours provide valuable insight on knowledge of malaria, access to care, and efficacy of malaria case management. Thus far, few studies have focused on central Mozambique. The aim was to describe community level Plasmodium falciparum prevalence and health-seeking behaviours among residents of Sussundenga, Mozambique, a rural village in Manica Province with high malaria incidence reported at the Sussundenga-Sede health centre (RHC).. A cross-sectional community-based survey was conducted from December 2019 to February 2020. A random household sampling method was used, based on enumerated households from satellite imagery. All consenting participants completed a survey about malaria risk, prevention, and health-seeking behaviours, and received a P. falciparum malaria rapid diagnostic test (RDT).. The study enrolled 358 individuals from 96 households. The P. falciparum prevalence was 31.6% (95% CI [26.6-36.5%]). Ninety-three percent of participants reported using the Sussundenga-Sede RHC for healthcare. Sixty-six percent of participants (N = 233) experienced at least one malaria symptom in the past month, with self-reported fever most frequently reported (19.3%). Of these, 176 (76.5%) sought care in a health facility and 174 (79%) received an RDT with 130 (63%) having a positive test. Of those with a positive RDT, 127 (97%) received artemether-lumefantrine. Following treatment, 123 (97%) participants' symptoms resolved within a median of 3 days (IQR: 3-5) ranging from 2 to 14 days. In this high transmission setting, a high proportion of participants recognized malaria related symptoms then received a proper diagnostic test and treatment in a health facility.. Future interventions that leverage this health-seeking behaviour and strengthen health systems for community interventions will improve malaria control and inform the efficacy of potential interventions at this particular international border.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cross-Sectional Studies; Humans; Malaria; Malaria, Falciparum; Mozambique; Patient Acceptance of Health Care; Plasmodium falciparum; Prevalence

Resistance to anti-malarial drugs is associated with polymorphisms in target genes and surveillance for these molecular markers is important to detect the emergence of mutations associated with drug resistance and signal recovering sensitivity to anti-malarials previously used.. The presence of polymorphisms in genes associated with Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated by Sanger sequencing, in 85 P. falciparum day of enrollment samples from a therapeutic efficacy study of artemether-lumefantrine conducted in 2018-2019 in Quibdo, Colombia. Samples were genotyped to assess mutations in pfcrt (codons 72-76), pfdhfr (codons 51, 59, 108, and 164), and pfdhps genes (codons 436, 437, 540, and 581). Further, the genetic diversity of infections using seven neutral microsatellites (NMSs) (C2M34, C3M69, Poly α, TA1, TA109, 2490, and PfPK2) was assessed.. All isolates carried mutant alleles for pfcrt (K76T and N75E), and for pfdhfr (N51I and S108N), while for pfdhps, mutations were observed only for codon A437G (32/73, 43.8%). Fifty samples (58.8%) showed a complete neutral microsatellites (NMS) profile. The low mean number of alleles (2 ± 0.57) per locus and mean expected heterozygosity (0.17 ± 0.03) showed a reduced genetic diversity. NMS multilocus genotypes (MMG) were built and nine MMG were identified.. Overall, these findings confirm the fixation of chloroquine and pyrimethamine-resistant alleles already described in the literature, implying that these drugs are not currently appropriate for use in Colombia. In contrast, mutations in the pfdhps gene were only observed at codon 437, an indication that full resistance to sulfadoxine has not been achieved in Choco. MMGs found matched the clonal lineage E variant 1 previously reported in northwestern Colombia.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Chloroquine; Codon; Colombia; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Pyrimethamine; Sulfadoxine

Drug resistance in

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Chloroquine; Ghana; Humans; Lumefantrine; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine

The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria.. Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations.. The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Middle Aged; Plasmodium knowlesi

Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016.. A total of 770 patients in Côte d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouaké), Ayamé and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group.. Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.. Thérapies contenant des dérivés de l’artémisinine et hémoglobine anormale : faut-il adapter le traitement ?. Contexte : Le traitement à base d’artémisinine chez les patients atteints de paludisme et présentant une hémoglobine anormale peut être inefficace en raison de leur particularité génétique, ce qui pourrait entraîner une résistance. L’objectif principal de cette étude était d’évaluer in vivo l’effet des dérivés de l’artémisinine sur la clairance du parasite en fonction des variantes érythrocytaires. La réponse in vivo a été étudiée à travers des données rétrospectives obtenues au cours d’un protocole d’efficacité de 42 jours artéméther-luméfantrine/artésunate-amodiaquine mené dans les années 2012 à 2016. Résultats : Un total de 770 patients en Côte d’Ivoire fréquentant les hôpitaux d’Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouaké), Ayamé et Yamoussoukro, présentant un paludisme aigu non compliqué à falciparum ont été sélectionnés pour un typage réussi de l’hémoglobine. Les génotypes HbAS, HbSS, HbAC et HbSC ont été trouvés. Le temps de clairance du parasite a été obtenu pour 414 patients. Dans la population avec une hémoglobine anormale, les densités parasitaires à l’admission et le taux de clairance parasitaire étaient significativement plus faibles dans le groupe HbSC par rapport au groupe HbAA (respectivement, p = 0,02 et p = 0,007). Le RCPA était de 100 % pour chaque groupe après correction par PCR au jour 42. La demi-vie du parasite et le temps nécessaire pour que la parasitémie initiale diminue de 50 et 99 % étaient plus longs pour le groupe HbSC (p < 0,05). L’étude a également examiné la prévalence des polymorphismes du gène K13 dans différents groupes de génotype d’hémoglobine. Un total de 185 et 63 échantillons ont été séquencés respectivement dans le groupe HbAA et chez les patients présentant une Hb anormale. Seules deux mutations non synonymes D559N et V510M ont été trouvées dans le groupe HbAA. Conclusion : Bien que cette étude ait prouvé la bonne efficacité de l’artéméther-luméfantrine et de l’artésunate amodiaquine dans le traitement du paludisme simple à Plasmodium falciparum chez les patients présentant une hémoglobine anormale, le retard accru de clairance parasitaire peut représenter une menace pour la santé de ces patients en relation avec la crise drépanocytaire, et peut favoriser la sélection de parasites résistants à l’artémisinine.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Cote d'Ivoire; Drug Combinations; Ethanolamines; Hemoglobins, Abnormal; Humans; Malaria, Falciparum; Plasmodium falciparum; Retrospective Studies; Treatment Outcome

Artemisinin-based combination therapy (ACT) has been the recommended first-line treatment for uncomplicated malaria in Mozambique since 2006, with artemether-lumefantrine (AL) and amodiaquine-artesunate (AS-AQ) as the first choice. To assess efficacy of currently used ACT, an in vivo therapeutic efficacy study was conducted.. The study was conducted in four sentinel sites: Montepuez, Moatize, Mopeia and Massinga. Patients between 6 and 59 months old with uncomplicated Plasmodium falciparum malaria (2000-200,000 parasites/µl) were enrolled between February and September of 2018, assigned to either an AL or AS-AQ treatment arm, and monitored for 28 days. A Bayesian algorithm was applied to differentiate recrudescence from new infection using genotyping data of seven neutral microsatellites. Uncorrected and PCR-corrected efficacy results at day 28 were calculated.. Totals of 368 and 273 patients were enrolled in the AL and AS-AQ arms, respectively. Of these, 9.5% (35/368) and 5.1% (14/273) were lost to follow-up in the AL and AS-AQ arms, respectively. There were 48 and 3 recurrent malaria infections (late clinical and late parasitological failures) in the AL and AS-AQ arms, respectively. The day 28 uncorrected efficacy was 85.6% (95% confidence interval (CI) 81.3-89.2%) for AL and 98.8% (95% CI 96.7-99.8%) for AS-AQ, whereas day 28 PCR-corrected efficacy was 97.9% (95% CI 95.6-99.2%) for AL and 99.6% (95% CI 97.9-100%) for AS-AQ. Molecular testing confirmed that 87.4% (42/48) and 33.3% (1/3) of participants with a recurrent malaria infection in the AL and AS-AQ arms were new infections; an expected finding in a high malaria transmission area. Adverse events were documented in less than 2% of participants for both drugs.. Both AL and AS-AQ have therapeutic efficacies well above the 90% WHO recommended threshold and remain well-tolerated in Mozambique. Routine monitoring of therapeutic efficacy should continue to ensure the treatments remain efficacious. Trial registration Clinicaltrials.gov: NCT04370977.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Humans; Infant; Malaria, Falciparum; Mozambique; Parasitemia; Safety; Treatment Outcome

Primaquine is a gametocytocidal drug recommended by the World Health Organization (WHO) in a single-low dose combined with artemisinin-based combination therapy (ACT) for the treatment and prevention of Plasmodium falciparum malaria transmission. Safety monitoring concerns and the lack of a universal validated and approved primaquine pharmacovigilance tool is a challenge for a national rollout in many countries. This study aimed to explore the acceptance, reliability and perceived effectiveness of the primaquine roll out monitoring pharmacovigilance tool (PROMPT).. This study was conducted in three dispensaries in the Coastal region of Eastern Tanzania. The study held six in-depth interviews with healthcare providers and six participatory focus group discussions with malaria patients (3) and parents/guardians of sick children (3). Participants were purposively sampled. Thematic analysis was conducted with the aid of NVivo qualitative analysis software.. The respondents' general acceptance and perceived effectiveness of the single-low dose primaquine and PROMPT was good. Screening procedure for treatment eligibility and explaining to patients about the possible adverse events was considered very useful for safety reasons. Crushing and dissolving of primaquine tablet to get the appropriate dose, particularly in children, was reported by all providers to be challenging. Transport costs and poor access to the health facility were the main reasons for a patient failing to return to the clinic for a scheduled follow-up visit. Treatment was perceived to be safe by both providers and patients and reported no case of a severe adverse event. Some providers were concerned with the haemoglobin drop observed on day 7.. Single-low dose primaquine was perceived to be safe and acceptable among providers and patients. PROMPT demonstrated to be a reliable and user-friendly tool among providers. Further validation of the tool by involving the National Malaria Control Programme is pivotal to addressing key challenges and facilitating primaquine adoption in the national policy.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Cross-Sectional Studies; Female; Focus Groups; Humans; Interviews as Topic; Malaria, Falciparum; Male; Middle Aged; Parents; Patient Care Team; Primaquine; Safety; Tanzania; Young Adult

Artemisinin derivatives are used globally in the management of falciparum malaria. Postartemisinin delayed haemolysis (PADH) is a recognised adverse event contributing to severe anaemia. To the best of our knowledge, we report the first recorded fatal case of PADH. A 60-year-old woman presented with two episodes of collapse at home and feeling generally unwell. She had recently been treated for uncomplicated falciparum malaria 1 month prior with artemether 80 mg/lumefantrine 480 mg in Congo. Her results on admission revealed an anaemia (haemoglobin 43 g/L), raised lactate dehydrogenase and positive direct antiglobulin test that suggested an intravascular haemolytic process. She made a capacitous decision to refuse blood products in line with her personal beliefs. Despite best supportive treatment, she did not survive. This case highlights the importance of postartemisinin follow-up and should encourage discussion and careful consideration of its use in the context of lack of access to/patient refusal of blood products.

Topics: Anemia, Hemolytic; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Middle Aged

Since the introduction of artemisinin-based combination therapy (ACT) in Ghana in 2005 there has been a surveillance system by the National Malaria Control Programme (NMCP) and the University of Ghana Noguchi Memorial Institute for Medical Research (UG-NMIMR) to monitor the therapeutic efficacy of ACTs for the treatment of uncomplicated malaria in the country. We report trends and determinants of failure following treatment of Ghanaian children with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) combinations.. Per protocol analyses as well as cumulative incidence of day 28 treatment failure from Kaplan Meier survival analyses were used to describe trends of failure over the surveillance period of 2005-2018. Univariable and multivariable cox regression analyses were used to assess the determinants of treatment failure over the period.. Day 28 PCR-corrected failure, following treatment with ASAQ, significantly increased from 0.0% in 2005 to 2.0% (95% CI: 1.1-3.6) in 2015 (p = 0.013) but significantly decreased to 0.4% (95% CI: 0.1-1.6) in 2018 (p = 0.039). Failure, following treatment with AL, decreased from 4.5% (95% CI: 2.0-9.4) in 2010 to 2.7% (95% CI: 1.4-5.1) in 2018, though not statistically significant (p = 0.426). Risk of treatment failure, from multivariable cox regression analyses, was significantly lower among children receiving ASAQ compared with those receiving AL (HR = 0.24; 95% CI: 0.11-0.53; p < 0.001); lower among children with no parasitaemia on day 3 compared with those with parasitaemia on day 3 (HR = 0.02; 95% CI: 0.01-0.13; p < 0.001); and higher among children who received ASAQ and had axillary temperature ≥ 37.5 °C on day 1 compared with those with axillary temperature < 37.5 °C (HR = 3.96; 95% CI: 1.61-9.75; p = 0.003).. Treatment failures for both ASAQ and AL have remained less than 5% (below WHO's threshold of 10%) in Ghana since 2005. Predictors of treatment failure that need to be considered in the management of uncomplicated malaria in the country should include type of ACT, day 3 parasitaemia, and day 1 axillary temperature of patients being treated.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ghana; Humans; Infant; Malaria; Malaria, Falciparum; Treatment Failure

In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019.. This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR.. There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene.. DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Uganda

Drug resistance remains a major challenge for the management of malaria. This study investigated the efficacy of antimalarial combination artemether-lumefantrine (AL) in the treatment of uncomplicated malaria in Bangui, Central African Republic.. An evaluative cross-sectional study was conducted between the 15th February and the 7th March 2017 in the Complexe Pédiatrique in Bangui among children aged 6 months to 15 years. Clinical outcome was classified according to WHO criteria as adequate clinical and parasitological response (ACPR), late parasitologic failure (LPF), late clinical failure (LCF), and early treatment failure (ETF). The occurrence of mutations in the K 13 gene was studied by PCR-RFLP.. A total of 55 patients were included. After PCR correction, ACPR at D28 was 97.8% and LCF was 2.2%. Treatment failures were due to new infections. No mutations in the K-13 gene associated with artemisinin resistance were identified. All participants had wild type alleles. The decrease of anemia and fever was substantial.. This study showed that AL remained efficacious and well-tolerated. However, all participants in Central African Republic had wild type alleles unlike contrary in Rwanda where a R561H mutation has been identified. A regular monitoring of efficacy and study of molecular markers of drug resistance to artemisinin is essential.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Central African Republic; Child; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria; Malaria, Falciparum; Mutation; Treatment Outcome

Postexposure prophylaxis using artemisinin-based combination therapy (ACT) was prescribed to a malaria-naive nurse who experienced an injury with a hollow needle previously used on a patient admitted for severe imported

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Female; Humans; Malaria, Falciparum; Needlestick Injuries; Post-Exposure Prophylaxis

The resistance of Plasmodium falciparum to antimalarial drugs remains a major impairment in the treatment and eradication of malaria globally. Following the introduction of artemisinin-based combination therapy (ACT), there have been reports of delayed parasite clearance. In Kenya, artemether-lumefantrine (AL) is the recommended first-line treatment of uncomplicated malaria. This study sought to assess the efficacy of AL after a decade of use as the preferred method of managing malarial infections in Kenya. We assessed clinical and parasitological responses of children under 5 years between May and November 2015 in Chulaimbo sub-County, Kisumu, Kenya. Patients aged between 6 and 60 months with uncomplicated P. falciparum mono-infection, confirmed through microscopy, were enrolled in the study. The patients were admitted at the facility for 3 days, treated with a standard dose of AL, and then put under observation for the next 28 days for the assessment of clinical and parasitological responses. Of the 90 patients enrolled, 14 were lost to follow-up while 76 were followed through to the end of the study period. Seventy-five patients (98.7%) cleared the parasitaemia within a period of 48 h while one patient (1.3%) cleared on day 3. There was 100% adequate clinical and parasitological response. All the patients cleared the parasites on day 3 and there were no re-infections observed during the stated follow-up period. This study, therefore, concludes that AL is highly efficacious in clearing P. falciparum parasites in children aged ≥6 and ≤60 months. The study, however, underscores the need for continued monitoring of the drug to forestall both gradual ineffectiveness and possible resistance to the drug in all target users.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child, Preschool; Female; Humans; Infant; Kenya; Malaria, Falciparum; Male; Plasmodium falciparum

The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy.. This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed.. Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64-83%) in Nanoro, 76% (66-83%) in Gourcy, and 92% (84-96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75-89%) in Gourcy, 89% (81-94%) in Nanoro, and 97% (92-99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation.. The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child, Preschool; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Quinolines

The use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether-lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso.. This study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model.. A total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy's law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms.. Pyronaridine-artesunate and artemether-lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas. Trial registration Pan African Clinical Trials Registry. PACTR201105000286876.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Burkina Faso; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Liver; Malaria, Falciparum; Male; Naphthyridines; Plasmodium falciparum

In sub-Saharan Africa, artemisinin-containing therapies for malaria treatment are regularly co-administered with ART. Currently, dolutegravir-based regimens are recommended as first-line therapy for HIV across most of Africa.. To investigate the population pharmacokinetics of dolutegravir during co-administration with artemether/lumefantrine or artesunate/amodiaquine, two commonly used antimalarial therapies.. We developed a population pharmacokinetic model of dolutegravir with data from 26 healthy volunteers in two Phase 2 studies with a total of 403 dolutegravir plasma concentrations at steady state. Volunteers received 50 mg of dolutegravir once daily alone or in combination with standard treatment doses of artemether/lumefantrine (80/480 mg) or artesunate/amodiaquine (200/540 mg).. A two-compartment model with first-order elimination and transit compartment absorption best described the concentration-time data of dolutegravir. Typical population estimates for clearance, absorption rate constant, central volume, peripheral volume and mean absorption transit time were 0.713 L/h, 1.68 h-1, 13.2 L, 5.73 L and 1.18 h, respectively. Co-administration of artemether/lumefantrine or artesunate/amodiaquine increased dolutegravir clearance by 10.6% (95% CI 4.09%-34.5%) and 26.4% (95% CI 14.3%-51.4%), respectively. Simulations showed that simulated trough concentrations of dolutegravir alone or in combination with artemether/lumefantrine or artesunate/amodiaquine are maintained above the dolutegravir protein-adjusted IC90 of 0.064 mg/L for more than 99% of the individuals.. Dolutegravir dose adjustments are not necessary for patients who are taking standard 3 day treatment doses of artemether/lumefantrine or artesunate/amodiaquine.

Topics: Africa; Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Drug Combinations; Ethanolamines; Fluorenes; Heterocyclic Compounds, 3-Ring; Humans; Malaria, Falciparum; Oxazines; Piperazines; Pyridones

As demonstrated in mathematical models, the simultaneous deployment of multiple first-line therapies (MFT) for uncomplicated malaria, using artemisinin-based combination therapies (ACTs), may extend the useful therapeutic life of the current ACTs. This is possible by reducing drug pressure and slowing the spread of resistance without putting patients' life at risk. We hypothesised that a simultaneous deployment of three different ACTs is feasible, acceptable and can achieve high coverage rate if potential barriers are properly identified and addressed.. We plan to conduct a quasi-experimental study in the Kaya health district in Burkina Faso. We will investigate a simultaneous deployment of three ACTs, artemether-lumefantrine, pyronaridine-artesunate, dihydroartesinin-piperaquine, targeting three segments of the population: pregnant women, children under five and individuals aged five years and above. The study will include four overlapping phases: the formative phase, the MFT deployment phase, the monitoring and evaluation phase and the post-evaluation phase. The formative phase will help generate baseline information and develop MFT deployment tools. It will be followed by the MFT deployment phase in the study area. The monitoring and evaluation phase will be conducted as the deployment of MFT progresses. Cross-sectional surveys including desk reviews as well as qualitative and quantitative research methods will be used to assess the study outcomes. Quantitatives study outcomes will be measured using univariate, bivariate and multivariate analysis, including logistic regression and interrupted time series analysis approach. Content analysis will be performed on the qualitative data.. The Health Research Ethics Committee in Burkina Faso approved the study (Clearance no. 2018-8-113). Study findings will be disseminated through feedback meetings with local communities, national workshops, oral presentations at congresses, seminars and publications in peer-reviewed scientific journals.. NCT04265573.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Cross-Sectional Studies; Drug Combinations; Feasibility Studies; Female; Humans; Malaria; Malaria, Falciparum; Pregnancy

Artemisinin-based combination therapy (ACT), such as artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine (DP), and artemether-lumefantrine (AL), is the first-line treatment for malaria in many malaria-endemic areas. However, we lack a detailed evaluation of the cardiotoxicity of these ACTs. This study aimed to analyze the electrocardiographic effects of these three ACTs in malaria patients.. We analyzed the clinical data of 89 hospitalized patients with falciparum malaria who had received oral doses of three different ACTs. According to the ACTs administered, these patients were divided into three treatment groups: 27 treated with AP (Artequick), 31 with DP (Artekin), and 31 with AL (Coartem). Electrocardiograms and other indicators were recorded before and after the treatment. The QT interval was calculated using Fridericia's formula (QTcF) and Bazett's formula (QTcB).. Both QTcF and QTcB interval prolongation occurred in all three groups. The incidence of such prolongation between the three groups was not significantly different. The incidence of both moderate and severe prolongation was not significantly different between the three groups. The ΔQTcF and ΔQTcB of the three groups were not significantly different. The intra-group comparison showed significant prolongation of QTcF after AL treatment.. Clinically recommended doses of DP, AL, and AP may cause QT prolongation in some malaria patients but do not cause torsades de pointes ventricular tachycardia or other arrhythmias.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Electrocardiography; Humans; Malaria; Malaria, Falciparum; Quinolines

Topics: Angola; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Humans; Malaria, Falciparum

In Nigeria, indiscriminate use of antimalarial drugs may contribute to the threat of drug resistance, but this has not been evaluated among people living with human immunodeficiency virus (HIV).. HIV-positive adults attending a university hospital HIV clinic and HIV-negative adult volunteers from the university hospital community with a positive blood film were treated with artemether-lumefantrine. Parasite DNA from before and after treatment was polymerase chain reaction amplified to identify molecular markers of drug susceptibility.. The pfcrt76T genotype was prevalent among both HIV-positive and HIV-negative participants (78.6% and 68.2%, respectively). Three new mutations in the pfmdr1 gene-F73S, S97L and G165R-and the uncommon pfdhps S436F variant were detected, whereas pfdhps K540E and pfdhfr I164L were absent. The A437G allele of pfdhps predominated (62/66 [94%]). The I431 V mutation was found in 19 of 66 pretreatment pfdhps sequences (28.8%). The pfmdr1 86N allele was significantly more common at day 3 post-treatment than at baseline (odds ratio 8.77 [95% confidence interval 1.21 to 380]).. We found evidence of continued chloroquine use among HIV-positive individuals. Selection for the pfmdr1 86N after artemether-lumefantrine treatment was observed, indicating a possible threat to antimalarial efficacy in the study area. The complexity of pfdhps haplotypes emphasises the need for careful monitoring of anti-folate susceptibility in Nigeria.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Drug Resistance; HIV; Humans; Malaria; Malaria, Falciparum; Nigeria; Plasmodium falciparum; Protozoan Proteins

Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether-lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes.. This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6-59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether-lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol.. 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88-100) in Masaka, 93·8% (85-98) in Rukara, and 97·2% (91-100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda.. We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether-lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered.. The US President's Malaria Initiative.. For the French translation of the abstract see Supplementary Materials section.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Resistance; Female; Genotype; Humans; Infant; Malaria, Falciparum; Male; Mutation, Missense; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Rwanda

Malaria is a major public health problem in India and accounts for about 88% of malaria burden in South-East Asia. India alone accounted for 2% of total malaria cases globally. Anti-malarial drug resistance is one of the major problems for malaria control and elimination programme. Artemether-lumefantrine (AL) is the first-line treatment of uncomplicated Plasmodium falciparum in north eastern states of India since 2013 after confirming the resistance against sulfadoxine-pyrimethamine. In the present study, therapeutic efficacy of artemether-lumefantrine and k13 polymorphism was assessed in uncomplicated P. falciparum malaria.. This study was conducted at four community health centres located in Koraput district of Odisha, Bastar district of Chhattisgarh, Balaghat district of Madhya Pradesh and Gondia district of Maharashtra state. Patients with uncomplicated P. falciparum malaria were administered with fixed dose combination (6 doses) of artemether-lumefantrine for 3 days and clinical and parasitological response was recorded up to 28 days as per World Health Organization protocol. Nucleotide sequencing of msp1 and msp2 gene was performed to differentiate between recrudescence and reinfection. Amplification and sequencing of k13 propeller gene region covering codon 450-680 was also carried out to identify the polymorphism.. A total 376 malaria patients who fulfilled the enrolment criteria as well as consented for the study were enrolled. Total 356 patients were followed up successfully up to 28 days. Overall, the adequate clinical and parasitological response was 98.9% and 99.4% with and without PCR correction respectively. No case of early treatment failure was observed. However, four cases (1.1%) of late parasitological failure were found from the Bastar district of Chhattisgarh. Genotyping of msp1 and msp2 confirmed 2 cases each of recrudescence and reinfection, respectively. Mutation analysis of k13 propeller gene showed one non-synonymous mutation Q613H in one isolate from Bastar.. The study results showed that artemether-lumefantrine is highly effective in the treatment of uncomplicated P. falciparum malaria among all age groups. No functional mutation in k13 was found in the study area. The data from this study will be helpful in implementation of artemether-lumefantrine in case of treatment failure by artesunate plus sulfadoxine-pyrimethamine.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Endemic Diseases; Female; Humans; India; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Young Adult

The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali.. Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000-200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing.. A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5-88.4%) in the AL arm and 93.1% (95% CI 89.7-96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0-95.9%) in the AL arm and 97.1% (93.6-100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common.. The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Mali

A recent randomized controlled trial, the WANECAM (West African Network for Clinical Trials of Antimalarial Drugs) trial, conducted at seven centers in West Africa, found that artemether-lumefantrine, artesunate-amodiaquine, pyronaridine-artesunate, and dihydroartemisinin-piperaquine all displayed good efficacy. However, artemether-lumefantrine was associated with a shorter interval between clinical episodes than the other regimens. In a further comparison of these therapies, we identified cases of persisting submicroscopic parasitemia by quantitative PCR (qPCR) at 72 h posttreatment among WANECAM participants from 5 sites in Mali and Burkina Faso, and we compared treatment outcomes for this group to those with complete parasite clearance by 72 h. Among 552 evaluable patients, 17.7% had qPCR-detectable parasitemia at 72 h during their first treatment episode. This proportion varied among sites, reflecting differences in malaria transmission intensity, but did not differ among pooled drug treatment groups. However, patients who received artemether-lumefantrine and were qPCR positive at 72 h were significantly more likely to have microscopically detectable recurrent Plasmodium falciparum parasitemia by day 42 than those receiving other regimens and experienced, on average, a shorter interval before the next clinical episode. Haplotypes of

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Burkina Faso; Drug Combinations; Ethanolamines; Humans; Malaria, Falciparum; Mali; Parasitemia; Plasmodium falciparum; Treatment Failure

Symptomatic malaria cases reflect only a small proportion of all Plasmodium spp infections. Many infected individuals are asymptomatic, and persistent asymptomatic Plasmodium falciparum infections are common in endemic settings. We aimed to quantify the contribution of symptomatic and asymptomatic infections to P falciparum transmission in Tororo, Uganda.. We did a longitudinal, observational cohort study in Tororo district, Uganda. We recruited participants of all ages from randomly selected households within this district. Participants were eligible if the selected household had no more than nine permanent residents and at least two members younger than 10 years, and the household was their primary residence, and they agreed to come to the study clinic for any fever episode and avoid antimalarial medications outside the study. Participants were followed-up by continuous passive surveillance for the incidence of symptomatic infections; routine assessments (ie, standardised clinical evaluation and blood samples) were done at baseline and at routine visits every 4 weeks for 2 years. P falciparum parasite density, gametocyte density, and genetic composition were determined molecularly using quantitative PCR (qPCR), quantitative reverse transcriptase PCR (qRT-PCR), and amplicon deep sequencing, respectively. Membrane feeding assays were also done to assess infectivity to mosquitoes. The contribution of different populations to the infectious reservoir was estimated for symptomatic infections, asymptomatic but microscopically detected infections, and asymptomatic but qPCR-detected infections; and for age groups younger than 5 years, 5-15 years, and 16 years or older.. Between Oct 4, 2017, and Oct 31, 2019, 531 individuals were enrolled from 80 randomly selected households and were followed-up for 2 years. At baseline, P falciparum was detected in 28 (5·3%) of 531 participants by microscopy and an additional 64 (12·1%) by qPCR and declined thereafter. In 538 mosquito feeding experiments on 107 individuals, 446 (1·2%) of 37 404 mosquitoes became infected, with mosquito infection rates being strongly associated with gametocyte densities (β=2·11, 95% CI 1·62-2·67; p<0·0001). Considering both transmissibility of infections and their relative frequency, the estimated human infectious reservoir consisted primarily of asymptomatic microscopy-detected infections (83·8%), followed by asymptomatic submicroscopic infections (15·6%), and symptomatic infections (0·6%). Children aged 5-15 years accounted for more than half of the infectious reservoir (58·7%); individuals younger than 5 years (25·8%) and those 16 years or older (15·6%) contributed less. Samples from four children contribued to 279 (62·6%) of 446 infected mosquitoes after multiple mosquito-feeding assays.. Individuals with asymptomatic infections were important drivers of malaria transmission. School-aged children contributed to more than half of all mosquito infections, with a small minority of asymptomatic children being highly infectious. Demographically targeted interventions, aimed at school-aged children, could further reduce transmission in areas under effective vector control.. US National Institutes of Health, Bill & Melinda Gates Foundation, and the European Research Council.

Topics: Adolescent; Animals; Anopheles; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Cohort Studies; Female; Humans; Longitudinal Studies; Malaria, Falciparum; Male; Plasmodium falciparum; Uganda

Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated. A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the. Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The. Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.

Topics: Alleles; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Protozoan Proteins

The failure of artemisinin combination therapy (ACT) in malaria patients returning from endemic regions may be driven by parasite resistance to this treatment. ACT is used globally as the first-line treatment for Plasmodium falciparum malaria. However, artemisinin-resistant strains of P. falciparum have emerged and spread across Southeast Asia, with the risk of reaching high malaria burden regions in Africa and elsewhere. Here, we report on two malaria imported cases from Africa with possible parasite resistance to the ACT artemether-lumefantrine (AL). Case presentation: Two middle-aged males returning from Angola and Mozambique developed malaria symptoms in Portugal, where they were diagnosed and received treatment with AL as hospital inpatients. After apparent cure and discharge from hospital, these individuals returned to hospital showing signs of late clinical failure. Molecular analysis was performed across a number of drug resistance associated genes. No evidence of pfk13-mediated artemisinin resistance was found. Both subjects had complete parasite clearance after treatment with non-ACT antimalarials. Conclusion: Our case-studies highlights the need for close monitoring of signs of unsatisfactory antimalarial efficacy among AL treated patients and the possible implication of other genes or mutations in the parasite response to ACTs.

Topics: Angola; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Humans; Malaria, Falciparum; Male; Middle Aged; Mozambique; Plasmodium falciparum; Treatment Failure

In 2005, artemether-lumefantrine (AL), an artemisinin-based combination therapy, was introduced as the first-line treatment of uncomplicated Plasmodium falciparum malaria in Benin. Per World Health Organization recommendations to monitor the efficacy of antimalarial treatment, we conducted a therapeutic efficacy study with AL for uncomplicated P. falciparum malaria in Bohicon and Kandi, Benin, from 2018 to 2019. Febrile patients aged 6 to 59 months with confirmed P. falciparum monoinfection received supervised doses of AL for 3 days. We monitored patients clinically and parasitologically on days 1, 2, 3, 7, 14, 21, and 28. A molecular analysis to detect mutations in the P. falciparum Kelch propeller gene (Pfk13) gene was carried out on day 0 samples. A total of 205 patients were included in the study. In Bohicon, the uncorrected adequate clinical and parasitological response (ACPR) proportion was 91.3% (95% confidence interval [CI]: 84.6-95.8%), whereas in Kandi this proportion was 96.7% (95% CI: 90.6-99.3%). Genotype-corrected ACPR proportions were 96.3% (95% CI: 90.9-99.0%) and 96.7% (95% CI: 90.6-99.3%) in Bohicon and Kandi, respectively. On day 3, 100% of patients in Bohicon and 98.9% of patients in Kandi had undetectable parasitemia. The C580Y mutation in the Pfk13 gene was not observed. AL remains effective for P. falciparum malaria in these two sites in Benin. Monitoring antimalarial efficacy and prevalence of molecular-resistance markers in Benin should be continued to allow for early detection of antimalarial resistance and to guide treatment policies.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Benin; Child, Preschool; DNA, Protozoan; Drug Resistance, Microbial; Female; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Treatment Outcome

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Humans; Malaria, Falciparum; Male; Travel; Treatment Failure

The emergence of artemisinin-resistant

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Female; Genotype; Humans; Malaria, Falciparum; Male; Middle Aged; Myanmar; Plasmodium falciparum; Quinolines; Young Adult

The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women.. A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz.. Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy.. Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Pregnancy; Prospective Studies; Uganda; Young Adult

Antimalarial drugs have long half-lives, so clinical trials to monitor their efficacy require long periods of follow-up to capture drug failure that may become patent only weeks after treatment. Reinfections often occur during follow-up, so robust methods of distinguishing drug failures (recrudescence) from emerging new infections are needed to produce accurate failure rate estimates. Molecular correction aims to achieve this by comparing the genotype of a patient's pretreatment (initial) blood sample with that of any infection that occurs during follow-up, with matching genotypes indicating drug failure. We use an

Topics: Algorithms; Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; Computational Biology; Computer Simulation; Data Interpretation, Statistical; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Microsatellite Repeats; Plasmodium falciparum; Reinfection; Treatment Failure

Artemisinin-based combination therapy (ACT) is the first-line antimalarial regimen in Indonesia. Susceptibility of

Topics: Alleles; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cross-Sectional Studies; Drug Resistance; Humans; Indonesia; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Protozoan Proteins

The efficacy of artemether-lumefantrine (AL) for treatment of uncomplicated Plasmodium falciparum malaria in south-western Ethiopia is poorly documented. Regular monitoring of drug efficacy is an important tool for supporting national treatment policies and practice. This study investigated the therapeutic efficacy of AL for the treatment of P. falciparum malaria in Ethiopia.. The study was a one-arm, prospective, evaluation of the clinical and parasitological, responses to directly observed treatment with AL among participants 6 months and older with uncomplicated P. falciparum malaria. Real-time polymerase chain reaction (PCR) and nested PCR reaction methods were used to quantify and genotype P. falciparum. A modified protocol based on the World Health Organization 2009 recommendations for the surveillance of anti-malarial drug efficacy was used for the study with primary outcomes, clinical and parasitological cure rates at day-28. Secondary outcomes assessed included patterns of fever and parasite clearance. Cure rate on day-28 was assessed by intention to treat (ITT) and per protocol (PP) analysis. Parasite genotyping was also performed at baseline and at the time of recurrence of parasitaemia to differentiate between recrudescence and new infection.. Of the 80 study participants enrolled, 75 completed the follow-up at day-28 with ACPR. For per protocol (PP) analysis, PCR-uncorrected and-corrected cure rate of AL among the study participants was 94.7% (95% CI 87.1-98.5) and 96% (95% CI 88.8-99.2), respectively. For intention to treat (ITT) analysis, the cure rate was 90% (95% CI 88.8-99.2). Based on Kaplan-Meier survival estimate, the cumulative incidence of failure rate of AL was 3.8% (95% CI 1.3-11.4). Only three participants 3.8% (95% CI 0.8-10.6) of the 80 enrolled participants were found to be positive on day-3. The day three-positive participants were followed up to day 28 and did not correspond to treatment failures observed during follow-up. Only 7.5% (6/80) of the participants were gametocyte-positive on enrollment and gametocytaemia was absent on day-2 following treatment with AL.. The therapeutic efficacy of AL is considerably high (above 90%). AL remained highly efficacious in the treatment of uncomplicated malaria in the study area resulted in rapid fever and parasite clearance as well as low gametocyte carriage rates despite the use of this combination for more than 15 years.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Ethiopia; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Prospective Studies; Young Adult

At the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in Southern Europe and America; many studies predicted a similar epidemic in Africa, as is currently seen in Europe and the United States of America. However, reported data have not confirmed these predictions. One of the hypotheses that could explain the later emergence and spread of COVID-19 pandemic in African countries is the use of antimalarial drugs to treat malaria, and specifically, artemisinin-based combination therapy (ACT).. The antiviral activity of fixed concentrations of ACT at concentrations consistent with those observed in human plasma when ACT is administered at oral doses for uncomplicated malaria treatment was evaluatedin vitro against a clinically isolated SARS-CoV-2 strain (IHUMI-3) in Vero E6 cells.. Mefloquine-artesunate exerted the highest antiviral activity with % inhibition of 72.1 ± 18.3 % at expected maximum blood concentration (C. Antimalarial drugs for which concentration data in the lungs are available are concentrated from 10 to 160 fold more in the lungs than in blood. Thesein vitro results reinforce the hypothesis that antimalarial drugs could be effective as an anti-COVID-19 treatment.

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Betacoronavirus; Chlorocebus aethiops; Coronavirus Infections; COVID-19; Drug Combinations; Humans; Malaria; Malaria, Falciparum; Mefloquine; Pandemics; Pneumonia, Viral; SARS-CoV-2; Vero Cells; Virus Replication

Currently, artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment in malaria-endemic areas. However, resistance in Plasmodium falciparum to artemisinin-based combinations emerging in the Greater Mekong Sub-region is a major problem hindering malaria elimination. To continuously monitor the potential spread of ACT-resistant parasites, this study assessed the efficacy of artemether-lumefantrine (AL) for falciparum malaria in western Myanmar.. Ninety-five patients with malaria symptoms from Paletwa Township, Chin State, Myanmar were screened for P. falciparum infections in 2015. After excluding six patients with a parasite density below 100 or over 150,000/µL, 41 P. falciparum patients were treated with AL and followed for 28 days. Molecular markers associated with resistance to 4-amino-quinoline drugs (pfcrt and pfmdr1), antifolate drugs (pfdhps and pfdhfr) and artemisinin (pfk13) were genotyped to determine the prevalence of mutations associated with anti-malarial drug resistance.. For the 41 P. falciparum patients (27 children and 14 adults), the 28-day AL therapeutic efficacy was 100%, but five cases (12.2%) were parasite positive on day 3 by microscopy. For the pfk13 gene, the frequency of NN insert after the position 136 was 100% in the day-3 parasite-positive group as compared to 50.0% in the day-3 parasite-negative group, albeit the difference was not statistically significant (P = 0.113). The pfk13 K189T mutation (10.0%) was found in Myanmar for the first time. The pfcrt K76T and A220S mutations were all fixed in the parasite population. In pfmdr1, the Y184F mutation was present in 23.3% of the parasite population, and found in both day-3 parasite-positive and -negative parasites. The G968A mutation of pfmdr1 gene was first reported in Myanmar. Prevalence of all the mutations in pfdhfr and pfdhps genes assessed was over 70%, with the exception of the pfdhps A581G mutation, which was 3.3%.. AL remained highly efficacious in western Myanmar. Pfk13 mutations associated with artemisinin resistance were not found. The high prevalence of mutations in pfcrt, pfdhfr and pfdhps suggests high-degree resistance to chloroquine and antifolate drugs. The pfmdr1 N86/184F/D1246 haplotype associated with selection by AL in Africa reached > 20% in this study. The detection of > 10% patients who were day-3 parasite-positive after AL treatment emphasizes the necessity of continuously monitoring ACT efficacy in western Myanmar.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Myanmar; Plasmodium falciparum; Young Adult

This study aims to evaluate the therapeutic efficacy and tolerance of two ACTs widely used for the treatment of uncomplicated malaria due to Plasmodium falciparum in Niger. The study was conducted from September to November 2017, at the Integrated Health Centers of Dogondoutchi and Birni N'Gaouré, in patients aged from 6 months to 15 years, with uncomplicated malaria due to Plasmodium falciparum. They were treated with either Artemether-Lumefantrine (AL) or Artesunate-Amodiaquine (ASAQ). The primary endpoint was the appropriate clinical and parasitological response (RCPA) to D28, after PCR correction. The secondary criteria were the clearing time of fever, parasites, and gametocytes and then the occurrence of adverse events. A total of 459 patients were examined, of whom 312 patients met the inclusion criteria for therapeutic efficacy evaluation. We have followed 299 patients up to J28 including 146 in the AL arm and 153 in the ASAQ arm. After PCR correction at J28, RCPA were 95.8% and 96% (P = 0.7185) for arms AL and ASAQ, respectively, compared to 93.1% and 94.1% respectively before PCR correction (P = 0.7892). The number of patients on AL and ASAQ treatment who developed an adverse reaction were 6 (7.6%) and 23 (28%) respectively. AL and ASAQ associations are effective and well tolerated. No serious adverse event was noted. However, their monitoring must continue to detect possible resistance.. Cette étude vise à évaluer l'efficacité thérapeutique et la tolérance de deux combinaisons thérapeutiques à base d'artémisinine (CTA), largement utilisées pour le traitement du paludisme non compliqué à Plasmodium falciparum au Niger. L'étude a été conduite de septembre à novembre 2017, au niveau des centres de santé intégrée (CSI) de Dogondoutchi et de Birni N'Gaouré, chez des patients âgés de 6 mois à 15 ans, atteints de paludisme non compliqué. Ils ont été traités par l'artéméther-luméfantrine (AL) ou l'artésunate–amodiaquine (ASAQ). Le critère de jugement principal était la réponse clinique et parasitologique adéquate (RCPA) à j28, après correction PCR. Les critères secondaires étaient le temps de clairance de la fièvre, des parasites et des gamétocytes puis la survenue des événements indésirables. Au total, 459 patients ont été examinés : 312 patients répondaient aux critères d'inclusion, 299 patients ont été suivis jusqu'à j28 dont 146 dans le bras AL, 153 dans le bras ASAQ. Les RCPA après correction PCR à j28 étaient de 95,8 et 96 % (p = 0,7185) respectivement pour AL et ASAQ alors qu'elles étaient respectivement de 93,1 et 94,1 % avant correction PCR (p = 0,7892). Le nombre de patients sous traitement AL et ASAQ ayant développé une réaction indésirable sont respectivement de 6, soit 7,6 %, et 23, soit 28 %. Les associations AL et ASAQ sont efficaces et bien tolérées, la première étant mieux tolérée. Aucun événement indésirable grave n'a été noté. Cependant, la surveillance des effets indésirables et de l'efficacité doit se poursuivre.Cette étude vise à évaluer l'efficacité thérapeutique et la tolérance de deux combinaisons thérapeutiques à base d'artémisinine (CTA), largement utilisées pour le traitement du paludisme non compliqué à Plasmodium falciparum au Niger. L'étude a été conduite de septembre à novembre 2017, au niveau des centres de santé intégrée (CSI) de Dogondoutchi et de Birni N'Gaouré, chez des patients âgés de 6 mois à 15 ans, atteints de paludisme non compliqué. Ils ont été traités par l'artéméther-luméfantrine (AL) ou l'artésunate–amodiaquine (ASAQ). Le critère de jugement principal était la réponse clinique et parasitologique adéquate (RCPA) à j28, après correction PCR. Les critères secondaires étaient le temps de clairance de la fièvre, des parasites et des gamétocytes puis la survenue des événements indésirables. Au total, 459 patients ont été examinés : 312 patients répondaient aux critères d'inclusion, 299 patients ont été sui

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Niger; Treatment Outcome

Antimalarial resistance is an inevitable feature of control efforts and a key threat to achieving malaria elimination. Plasmodium falciparum, the deadliest of several species causing human malaria, has developed resistance to essentially all antimalarials. This study sought to investigate the prevalence of molecular markers associated with resistance to sulfadoxine-pyrimethamine (SP) and artemether-lumefantrine (AL) in Southern and Western provinces in Zambia. SP is used primarily for intermittent preventive treatment during pregnancy, while AL is the first-line antimalarial for uncomplicated malaria in Zambia. Blood samples were collected from household members of all ages in a cross-sectional survey conducted during peak malaria transmission, April to May of 2017, and amplified by polymerase chain reaction (PCR). Amplicons were then analysed by high-resolution melt following PCR to identify mutations associated with SP resistance in the P. falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps) genes and lumefantrine resistance in the P. falciparum multi-drug resistance 1 (Pfmdr1) gene. Finally, artemether resistance was assessed in the P. falciparum Kelch 13 (PfK13) gene using nested PCR followed by amplicon sequencing. The results showed a high frequency of genotypic-resistant Pfdhps A437G (93.2%) and Pfdhfr C59R (86.7%), N51I (80.9%), and S108N (80.8%) of which a high proportion (82.4%) were quadruple mutants (Pfdhfr N51I, C59R, S108N +Pfdhps A437G). Pfmrd1 N86Y, Y186F, and D1246Y - NFD mutant haplotypes were observed in 41.9% of isolates. The high prevalence of quadruple dhps/dhfr mutants indicates strong antifolate drug pressure from SP or other drugs (e.g., co-trimoxazole). Three samples contained PfK13 mutations, two synonymous (T478 and V666) and one non-synonymous (A578S), none of which have been associated with delayed clearance. This suggests that artemisinin remains efficacious in Zambia, however, the moderately high prevalence of approximately 40% Pfmdr1 NFD mutations calls for close monitoring of AL.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Cross-Sectional Studies; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase

Artemether-lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child, Preschool; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Zambia

Nigeria bears 25% of global malaria burden despite concerted efforts towards its control and elimination. The emergence of drug resistance to first line drugs, artemisinin combination therapies (ACTs), indicates an urgent need for continuous molecular surveillance of drug resistance especially in high burden countries where drug interventions are heavily relied on. This study describes mutations in Plasmodium falciparum genes associated with drug resistance in malaria; Pfk13, Pfmdr1, PfATPase6 and Pfcrt in isolates obtained from 83 symptomatic malaria patients collected in August 2014, aged 1-61 years old from South-west Nigeria.. Two Pfmdr1, N86 and Y184 variants were present at a prevalence of 56% and 13.25% of isolates respectively. There was one synonymous (S679S) and two non-synonymous (M699V, S769M) mutations in the PATPase6 gene, while Pfcrt genotype (CVIET), had a prevalence of 45%. The Pfk13 C580Y mutant allele was suspected by allelic discrimination in two samples with mixed genotypes although this could not be validated with independent isolation or additional methods. Our findings call for robust molecular surveillance of antimalarial drug resistance markers in west Africa especially with increased use of antimalarial drugs as prophylaxis for Covid-19.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Calcium-Transporting ATPases; Child; Child, Preschool; Coronavirus Infections; COVID-19; Drug Resistance; Female; Gene Expression; Genotype; Humans; Infant; Malaria, Falciparum; Membrane Transport Proteins; Middle Aged; Molecular Epidemiology; Multidrug Resistance-Associated Proteins; Mutation; Nigeria; Pandemics; Plasmodium falciparum; Pneumonia, Viral; Protozoan Proteins

Ethiopia has set a goal to eliminate malaria by 2030; Artemether-lumefantrine (AL) is put as one of the cornerstone strategies for uncomplicated plasmodium falciparum malaria treatment. However, only focusing on prescribing of the treatment without assessing patients' adherence could lead to the resistance of the drug. In Ethiopia, there is limited evidence about patients' adherence to AL and its influencing factors. Therefore, this study aimed at addressing this information gap.. A health facility based cross-sectional study was employed. Participants were selected using simple random sampling technique from registration books of the public health facilities in AsgedeTsimbla. Data were collected from March 24th to April 30th, 2018. We interviewed participants using a pre-tested structured questionnaire, and the blister pack was also inspected at their homes on day 4. Data were entered into Epi-Info and analyzed using SPSS 21. Odds ratios with 95% Confidence Intervals were estimated and the level of significance was declared at p-value ≤ 0.05.. A total of 384 study participants were interviewed with a response rate of 95.5%. The overall AL adherence was 53.6% (95% CI 48.4-58.3%). Children aged < 5 years [AOR: 0.4, 95% CI (0.2-0.8)], and being treated in health post [AOR: 0.3, 95% CI (0.1-0.5)] were more likely to show AL adherence whereas illiteracy [AOR: 9.4, 95% CI (4.2-21.3)], didn't know the consequence of discontinued AL [AOR: 4.0, 95% CI (2.1-7.6)], had concomitant drugs [AOR: 2.5, 95% CI (1.4-4.5)], and stopped/saved drug when improved before tablet got finished [AOR: 3.2, 95% CI (1.7-5.9)] were factors less likely to be associated with AL adherence.. AL adherence was low. Children aged < 5 years, and being treated in health post were determinants of AL adherence whereas illiteracy, didn't know the consequence of discontinued the drug, had concomitant drugs, and stopped/saved drug when improved before tablet got finished were factors that hindered the AL adherence. Stakeholders should emphasize designing appropriate strategies including educational interventions to increase the AL adherence and prevent drug resistance. Further research should be conducted to evaluate AL resistance.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Infant; Malaria, Falciparum; Male; Medication Adherence; Middle Aged; Public Health; Young Adult

Single nucleotide polymorphisms occurring in the Plasmodium falciparum multidrug resistant gene 1 (pfmdr1) are known to be associated with aminoquinoline resistance and, therefore, represent key P. falciparum markers for monitoring resistance both in susceptible groups (children under 5 years old and pregnant women) and in the general population. This study aimed to determine prevalence and factors associated with the carriage of pfmdr1 N86Y, Y184F and D1246Y polymorphisms among pregnant women in a setting of high malaria transmission in Burkina Faso.. Plasmodium falciparum isolates were collected at the first antenatal care visit (ANC-1) as well as at delivery from pregnant women participating in the COSMIC trial (NTC01941264), which assessed malaria preventive interventions during pregnancy in the Nanoro Health District. Here, pregnant women received intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and malaria infections and/or diseases were treated using artemether-lumefantrine (AL) during the trial. Parasite DNA was extracted from dried blood spots and the presence of pfmdr1 mutations at positions 86, 184 and 1246 was determined using nested PCR, followed by restriction fragment length polymorphism (RFLP) analysis.. A prevalence of 13.2% (20/151) and 12.1% (14/116) of the pfmdr1 86Y mutant allele was found at ANC-1 and at delivery, respectively, while no mutant allele was observed for Y184F and D1246Y codons at both ANC-1 and at delivery. There were no significant factors associated with pfmdr1 86Y mutant allele carriage at ANC-1. However, malaria infections at delivery with a parasite density above the median (2237.2 (IQR: 613.5-11,425.7) parasites/µl) was associated with an increase risk of pfmdr1 86Y mutant allele carriage (AOR = 5.5 (95% CI  1.07-28.0); P = 0.04). In contrast, both three or more IPTp-SP doses (AOR = 0.25 (95% CI 0.07-0.92); P = 0.04) and one or more AL treatment (AOR = 0.25 (95% CI 0.07-0.89); P = 0.03) during pregnancy were associated with a significant reduce risk of pfmdr1 86Y mutant allele carriage at delivery.. These findings suggest that both high coverage of IPTp-SP and the use of AL for the treatment of malaria infection/disease during pregnancy select for pfmdr1 N86 wild-type allele at delivery.

Topics: Adolescent; Adult; Artemether, Lumefantrine Drug Combination; Burkina Faso; Carrier State; Drug Combinations; Female; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Pregnancy; Prevalence; Pyrimethamine; Risk Factors; Sulfadoxine; Young Adult

The analysis of single nucleotide polymorphism (SNPs) in drug-resistance associated genes is a commonly used strategy for the surveillance of anti-malarial drug resistance in populations of parasites. The present study was designed and performed to provide genetic epidemiological data of the prevalence of N86Y-Y184F-D1246Y SNPs in Plasmodium falciparum multidrug resistance 1 (pfmdr1) in the malaria hotspot of Northern Nigeria.. Plasmodium falciparum-positive blood samples on Whatman-3MM filter papers were collected from 750 symptomatic patients from four states (Kano, Kaduna, Yobe and Adamawa) in Northern Nigeria, and genotyped via BigDye (v3.1) terminator cycle sequencing for the presence of three SNPs in pfmdr1. SNPs in pfmdr1 were used to construct NYD, NYY, NFY, NFD, YYY, YYD, YFD and YFY haplotypes, and all data were analysed using Pearson Chi square and Fisher's exact (FE) tests.. The prevalence of the pfmdr1 86Y allele was highest in Kaduna (12.50%,. The present study suggests that strains of P. falciparum with reduced sensitivity to the lumefantrine component of AL exist in Northern Nigeria and predominate in the North-West region.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Drug Resistance, Multiple; Genes, MDR; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Nigeria; Plasmodium falciparum; Polymorphism, Genetic

As September marks the start of the malaria season in South Africa (SA), it is essential that healthcare professionals consider both COVID- 19 and malaria when a patient who lives in or has recently travelled to a malaria area presents with acute febrile illness. Early diagnosis of malaria by either a rapid diagnostic test or microscopy enables prompt treatment with the effective antimalarial, artemether-lumefantrine, preventing progression to severe disease and death. Intravenous artesunate is the preferred treatment for severe malaria in both children and adults. Adding single low-dose primaquine to standard treatment is recommended in endemic areas to block onward transmission. Use of the highly effective artemisinin-based therapies should be limited to the treatment of confirmed malaria infections, as there is no clinical evidence that these antimalarials can prevent or treat COVID-19. Routine malaria case management services must be sustained, in spite of COVID-19, to treat malaria effectively and support SA's malaria elimination efforts.

Topics: Administration, Intravenous; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artesunate; COVID-19; Early Diagnosis; Early Medical Intervention; Humans; Malaria; Malaria, Falciparum; Microscopy; Point-of-Care Testing; Primaquine; Protozoan Proteins; SARS-CoV-2; Severity of Illness Index; South Africa

Malaria is a public health problem compounded with a widespread emergence of drug-resistant Plasmodium falciparum which necessitated the formulation of a new antimalarial drug policy (AMP).. This study was designed to assess adherence to the policy among physicians in health facilities in Delta state, Nigeria.. Cross-sectional, analytic study. Data were collected with a semi-structured questionnaire.. Two secondary and one tertiary health facilities in Delta State, Nigeria.. Physicians selected with a simple random technique from the facilities.. Prescribing pattern of antimalarial drugs and adherence to WHO treatment guideline among doctors.. Majority (90.8%) of respondents believed the antimalarial policy (AMP) should be strictly adhered to, although three-fifth (61.0%) of them rated its performance as poor. The level of adherence to the national antimalarial drug policy was high (78.5%) as most doctors prescribed Arthemeter-Lumefantrine, AL for uncomplicated malaria however barely two-fifth (35.4%) adhered to prescribing injectable Artesunate for complicated malaria. AL, (71.9%) was the most prescribed antimalarial drug for uncomplicated malaria The most prescribed antimalarial drugs for complicated malaria was artesunate (40.0%) followed by quinine (27.6%) and artemether (26.7%); although, chloroquine was also prescribed.. The level of adherence to AMP among doctors was sub-optimal. Continuous education of doctors on the new AMP is needed to achieve malarial control.. No funding was received for this study.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artesunate; Chloroquine; Drug Resistance, Microbial; Female; Guideline Adherence; Health Policy; Humans; Malaria, Falciparum; Male; Middle Aged; Nigeria; Plasmodium falciparum; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quinine; Surveys and Questionnaires; Young Adult

In non-anaemic children with malaria, early-appearing anaemia (EAA) is common following artemisinin-based combination treatments (ACTs) and it may become persistent (PEAA). The factors contributing to and kinetics of resolution of the deficit in haematocrit from baseline (DIHFB) characteristic of ACTs-related PEAA were evaluated in 540 consecutive children with malaria treated with artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine. Asymptomatic PEAA occurred in 62 children. In a multiple logistic regression model, a duration of illness ≤3 days before presentation, haematocrit <35% before and <25% one day after treatment initiation, drug attributable fall in haematocrit ≥6%, and treatment with dihydroartemisinin-piperaquine independently predicted PEAA. Overall, mean DIHFB was 5.7% (95% CI 4.8-6.6) 7 days after treatment initiation and was similar for all treatments. Time to 90% reduction in DIHFB was significantly longer in artemether-lumefantrine-treated children compared with other treatments. In a one compartment model, declines in DIHFB were monoexponential with overall mean estimated half-time of 3.9 days (95% CI 2.6-5.1), Cmax of 7.6% (95% CI 6.7-8.4), and Vd of 0.17 L/kg (95% CI 0.04-0.95). In Bland-Altman analyses, overall mean anaemia recovery time (AnRT) of 17.4 days (95% CI 15.5-19.4) showed insignificant bias with 4, 5 or 6 multiples of half-time of DIHFB. Ten children after recovery from PEAA progressed to late-appearing anaemia (LAA). Progression was associated with female gender and artesunate-amodiaquine treatment. Asymptomatic PEAA is common following ACTs. PEAA or its progression to LAA may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials. Trial registration: Pan Africa Clinical Trial Registration PACTR201709002064150, 1 March 2017 http://www.pactr.org.

Topics: Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Disease Progression; Drug Combinations; Female; Hematocrit; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Sex Factors; Treatment Outcome

Artemisinin-based combination therapy is currently the best option for the treatment of uncomplicated malaria. Quinine is recommended as a rescue treatment. Safety information during repeated treatment with the same drug is scarce. We report safety data from the Quinact randomized clinical trial (RCT) that was designed to assess efficacy and safety of artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL) and quinine+clindamycin (QnC).. Males and females aged 12 to 59 months with uncomplicated malaria were treated with ASAQ and followed up during 42 days (preRCT). Clinical failures were randomized to one of the 3 treatments and followed up for 28 days (RCT). Subsequent failures were repeatedly treated with ASAQ several times as needed (postRCT1, postRCT2 and so on) until a 28-days follow up period without parasitaemia.. Eight hundred and sixty-five, 242 and 64 patients were recruited respectively in preRCT, RCT and postRCTs. In preRCT, 433 (50.0%) patients experienced at least one drug-related adverse event (AE). The most reported AEs were anorexia (22.9%), asthenia (19.4%), and abnormal behavior (14.6%). Twenty-nine AEs (3.5%) were reported to be severe. In RCT, at least one drug-related AE was reported in 54.7%, 21.5% and 40.0% of patient randomized respectively to ASAQ, AL and QnC (p<0.001). During postRCT1 (n = 64), postRCT 2 (n = 17) and postRCT3 (n = 7), respectively 32.8%, 35.3% and 71.4% of patients experienced at least one drug-related AE. Three serious adverse events occurred but not judged related to study medication.. The proportion of AEs did not increase over the treatment courses with ASAQ. However, continuous monitoring is important.

Topics: Amodiaquine; Anti-Bacterial Agents; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child, Preschool; Clindamycin; Democratic Republic of the Congo; Drug Combinations; Female; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Plasmodium falciparum; Quinine

Plasmodium falciparum and P. vivax co-exist at different endemicity levels across Ethiopia. For over two decades Artemether-Lumefantrine (AL) is the first line treatment for uncomplicated P. falciparum, while chloroquine (CQ) is still used to treat P. vivax. It is currently unclear whether a shift from CQ to AL for P. falciparum treatment has implications for AL efficacy and results in a reversal of mutations in genes associated to CQ resistance, given the high co-endemicity of the two species and the continued availability of CQ for the treatment of P. vivax. This study thus assessed the prevalence of Pfcrt-K76T and Pfmdr1-N86Y point mutations in P. falciparum. 18S RNA gene based nested PCR confirmed P. falciparum samples (N = 183) collected through community and health facility targeted cross-sectional surveys from settings with varying P. vivax and P. falciparum endemicity were used. The proportion of Plasmodium infections that were P. vivax was 62.2% in Adama, 41.4% in Babile, 30.0% in Benishangul-Gumuz to 6.9% in Gambella. The Pfcrt-76T mutant haplotype was observed more from samples with higher endemicity of P. vivax as being 98.4% (61/62), 100% (31/31), 65.2% (15/23) and 41.5% (22/53) in samples from Adama, Babile, Benishangul-Gumuz and Gambella, respectively. However, a relatively higher proportion of Pfmdr1-N86 allele (77.3-100%) were maintained in all sites. The observed high level of the mutant Pfcrt-76T allele in P. vivax co-endemic sites might require that utilization of CQ needs to be re-evaluated in settings co-endemic for the two species. A country-wide assessment is recommended to clarify the implication of the observed level of variation in drug resistance markers on the efficacy of AL-based treatment against uncomplicated P. falciparum malaria.

Topics: Adolescent; Adult; Alleles; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Chloroquine; Drug Resistance; Endemic Diseases; Ethiopia; Female; Haplotypes; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Plasmodium vivax; Point Mutation; Polymorphism, Genetic; Prevalence; Protozoan Proteins; Young Adult

Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Treatment Failure; Young Adult

The efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) against asexual parasites population has been documented. However, the effect of these anti-malarials on sexual parasites is still less clear. Gametocyte clearance following treatment is essential for malaria control and elimination efforts; therefore, the study sought to determine trends in gametocyte clearance after AL or DP treatment in children from a malaria-endemic site in Kenya.. Children aged between 0.5 and 12 years from Busia, western Kenya with uncomplicated Plasmodium falciparum malaria were assigned randomly to AL or DP treatment. A total of 334 children were enrolled, and dried blood spot samples were collected for up to 6 weeks after treatment during the peak malaria transmission season in 2016 and preserved. Plasmodium falciparum gametocytes were detected by qRT-PCR and gametocyte prevalence, density and mean duration of gametocyte carriage were determined.. At baseline, all the 334 children had positive asexual parasites by microscopy, 12% (40/334) had detectable gametocyte by microscopy, and 83.7% (253/302) children had gametocytes by RT-qPCR. Gametocyte prevalence by RT-qPCR decreased from 85.1% (126/148) at day 0 to 7.04% (5/71) at day 42 in AL group and from 82.4% (127/154) at day 0 to 14.5% (11/74) at day 42 in DP group. The average duration of gametocyte carriage as estimated by qRT-PCR was slightly shorter in the AL group (4.5 days) than in the DP group (5.1 days) but not significantly different (p = 0.301).. The study identifies no significant difference between AL and DP in gametocyte clearance. Gametocytes persisted up to 42 days post treatment in minority of individuals in both treatment arms. A gametocytocidal drug, in combination with artemisinin-based combination therapy, will be useful in blocking malaria transmission more efficiently.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Female; Humans; Infant; Kenya; Malaria, Falciparum; Male; Plasmodium falciparum; Prevalence; Quinolines

Few data exist on the incidence or duration of natural Plasmodium falciparum infections in high-transmission settings. School-aged children (SAC) carry a disproportionate burden of infections, suggesting either increased incidence or increased duration. We estimated the incidence and duration of unique infections according to age groups. The Mfera Cohort Study (2014-2017) in Malawi had 2 years of follow-up, with 120 participants tested monthly and during sick visits. Blood samples were collected to detect P. falciparum by microscopy and polymerase chain reaction. Positive samples underwent genotyping. Simulation was used to account for high rates of nondetection of infection among low-parasitemia infections, which increase in frequency with age. Adults had significantly fewer unique infections per person per year (median, 2.5) compared with SAC and children younger than 5 years of age (6.3 and 6.6, respectively). Over half of all genotypes were persistent. Infections lasted significantly longer in adults (median, 180 days) and SAC (median, 163 days) compared with children younger than 5 years of age (median, 97 days), after accounting for age-dependent nondetection of infection. SAC acquired new infections at the same rate as children younger than 5 years, but they maintained these infections for longer periods of time, similar to adults. This study provides new insights into P. falciparum infection dynamics that should be considered when designing malaria control strategies.

Topics: Adolescent; Adult; Age Factors; Aged; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Female; Genotype; Humans; Incidence; Infant; Insecticide-Treated Bednets; Longitudinal Studies; Malaria, Falciparum; Malawi; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Seasons; Young Adult

The potential spread of antimalarial drug resistance to Africa, in particular for artemisinins and key partner drugs, is a major concern. We surveyed

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Aspartic Acid Endopeptidases; Child; Chloroquine; Drug Resistance; Folic Acid Antagonists; Humans; Lumefantrine; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Quinolines; Uganda

Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with antimalarials is hampered by important variations of heart rate during malaria crises and previous studies have reported highly variable values of QTc prolongations with ACTs. We assessed QTc prolongation with four ACTs, using high quality ECG recording and measurement techniques, during the first episode of malaria in 2,091 African patients enrolled in the WANECAM study which also monitored clinical safety. Using an original and robust method of QTc assessment, independent from heart rate changes and from the method of QT correction, we were able to accurately assess the extent of mean maximum QTc prolongation with the four ACTs tested. There was no evidence of proarrhythmia with any treatment during the study although dihydroartemisinin-piperaquine, artesunate-amodiaquine and artemether-lumefantrine significantly prolonged QTc. The extent of prolongation of ventricular repolarization can be accurately assessed in studies where heart rate changes impede QTc assessment.

Topics: Adolescent; Amodiaquine; Antimalarials; Arrhythmias, Cardiac; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Heart Rate; Humans; Long QT Syndrome; Malaria; Malaria, Falciparum; Male; Quinolines; Young Adult

Delayed parasite clearance and, consequently, reduced efficacy of artemisinin-based combination therapies have been linked with Plasmodium falciparum K13 gene SNPs in Southeast Asia. In Africa, significantly prolonged clearance has not yet been observed and the presently restricted variation in parasite clearance cannot be explained by K13 polymorphisms.. Our aim was to study the in vivo pfK13 transcriptional response in patients treated with artemether-lumefantrine and explore whether the pfk13 transcripts can explain the patients' parasite clearance outcomes.. A total of 47 Tanzanian children with microscopically confirmed uncomplicated P. falciparum malaria were hospitalized and received artemether-lumefantrine treatment (clinical trial ID: NCT00336375). RNA was extracted from venous blood samples collected before treatment initiation and at five more timepoints after treatment. cDNA was synthesized and pfk13 transcripts measured by real-time PCR.. A wide range of pfk13 transcript variation was observed throughout all timepoints after artemether-lumefantrine treatment. Taking parasite clearance data together with the pfk13 transcripts profile, we observed a negative correlation inferring that pfk13 down-regulation is associated with longer parasite clearance time.. The findings suggest that a reduced PfK13 transcriptional response may represent a first step towards artemisinin tolerance/resistance.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Drug Tolerance; Female; Gene Expression; Gene Expression Profiling; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Protozoan Proteins; Tanzania; Treatment Outcome

To determine the prevalence of Plasmodium falciparum multi-drug resistant gene-1 (Pfmdr-1) N86Y and D1246Y genotypes among febrile malaria outpatients attending Lira Regional Referral Hospital, Uganda.. Overall, 92.3% (n = 48/52) and 90% (n = 45/50) of the parasites detected carried the wild type alleles 1246D and N86, respectively. Only 7.7% (n = 4/52) and 10% (n = 5/50) of these P. falciparum isolates carried the Pfmdr-1 mutant alleles 1246Y and 86Y, respectively. Our results show high prevalence of wild type alleles N86 and D1246 in P. falciparum isolates from Lira Regional Referral Hospital, which could translate to a decreased sensitivity to artemether-lumefantrine. Continued monitoring of prevalence of single nucleotide polymorphisms is warranted to timely inform malaria treatment policies and guidelines.

Topics: Alleles; Antimalarials; Artemether, Lumefantrine Drug Combination; Drug Resistance; Fever; Gene Expression; Genotype; Hospitals; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Outpatients; Plasmodium falciparum; Polymorphism, Single Nucleotide; Prevalence; Uganda

Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub-Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic (PK)-pharmacodynamic study included 131 SAM and 266 non-SAM children administered artemether-lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit-absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the PK model. Mid-upper arm circumference was associated with decreased absorption of lumefantrine (25.4% decreased absorption per 1 cm reduction). Risk of recurrent malaria episodes (i.e., reinfection) were characterized by an interval-censored time-to-event model with a sigmoid maximum-effect model describing the effect of lumefantrine. SAM children were at risk of underexposure to lumefantrine and an increased risk of malaria reinfection compared with well-nourished children. Research on optimized regimens should be considered for malaria treatment in malnourished children.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Child, Preschool; Female; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Recurrence; Severe Acute Malnutrition

Routine surveillance on the therapeutic efficacy of artemisinin-based combination therapy (ACT) has been ongoing in Ghana since 2005. The sixth round of surveillance was conducted between 2015 and 2017 to determine the therapeutic efficacy of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) in 10 sentinel sites across the country.. The study was a one-arm, prospective, evaluation of the clinical, parasitological, and haematological responses to directly observed treatment with AS-AQ and AL among children 6 months to 9 years old with uncomplicated falciparum malaria. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used for the study with primary outcomes as prevalence of day 3 parasitaemia and clinical and parasitological cure rates on day 28. Secondary outcomes assessed included patterns of fever and parasite clearance as well as changes in haemoglobin concentration.. Day 3 parasitaemia was absent in all sites following treatment with AS-AQ whilst only one person (0.2%) was parasitaemic on day 3 following treatment with AL. Day 28 PCR-corrected cure rates following treatment with AS-AQ ranged between 96.7% (95% CI 88.5-99.6) and 100%, yielding a national rate of 99.2% (95% CI 97.7-99.7). Day 28 PCR-corrected cure rates following treatment with AL ranged between 91.3% (95% CI 79.2-97.6) and 100%, yielding a national rate of 96% (95% CI 93.5-97.6). Prevalence of fever declined by 88.4 and 80.4% after first day of treatment with AS-AQ and AL, respectively, whilst prevalence of parasitaemia on day 2 was 2.1% for AS-AQ and 1.5% for AL. Gametocytaemia was maintained at low levels (< 5%) during the 3 days of treatment. Post-treatment mean haemoglobin concentration was significantly higher than pre-treatment concentration following treatment with either AS-AQ or AL.. The therapeutic efficacy of AS-AQ and AL is over 90% in sentinel sites across Ghana. The two anti-malarial drugs therefore remain efficacious in the treatment of uncomplicated malaria in the country and continue to achieve rapid fever and parasite clearance as well as low gametocyte carriage rates and improved post-treatment mean haemoglobin concentration.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Ghana; Humans; Infant; Malaria, Falciparum; Male; Prospective Studies; Treatment Outcome

Blood smear microscopy remains the gold-standard method to diagnose and quantify malaria parasite density. In addition, parasite genotyping of select loci is the most utilized method for distinguishing recrudescent and new infections and to determine the number of strains per sample. In research settings, blood may be obtained from capillary or venous compartments, and results from these matrices have been used interchangeably. Our aim was to compare quantitative results for parasite density and strain complexity from both compartments.. In a prospective observational study, children and adults presenting with uncomplicated Plasmodium falciparum malaria, simultaneous capillary and venous blood smears and dried blood spots were collected over 42-days following treatment with artemether-lumefantrine. Blood smears were read by two microscopists, any discrepancies resolved by a third reader. Parasite DNA fingerprinting was conducted using six microsatellites. Bland Altman analysis and paired t-test/McNemar's test were used to assess the difference in density readings and measurements.. Two hundred twenty-three participants were included in the analysis (177 children (35 HIV-infected/142 HIV-uninfected), 21 HIV-uninfected pregnant women, and 25 HIV-uninfected non-pregnant adults). Parasite density measurements did not statistically differ between capillary and venous blood smears at the time of presentation, nor over the course of 42-day follow-up. Characterization of merozoite surface protein-2 (MSP-2) genetic polymorphism demonstrated a higher level of strain diversity at the time of presentation in venous samples, as compared with capillary specimens (p = 0.02). There was a high degree of variability in genotype-corrected outcomes when pairs of samples from each compartment were compared using MSP-2 alone, although the variability was reduced with the use of multiple markers.. Parasite density measurements do not statistically differ between capillary and venous compartments in all studied demographic groups at the time of presentation with malaria, or over the course of follow-up. More strains were detected by MSP-2 genotyping in venous samples than in capillary samples at the time of malaria diagnosis. The use of multiple polymorphic markers reduces the impact of variability in strain detection on genotype-corrected outcomes. This study confirms that both capillary and venous compartments can be used for sampling with confidence in the clinical research setting.. The trial was registered at ClinicalTrials.gov under registration no. NCT01717885 .

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Capillaries; Child; Child, Preschool; Drug Monitoring; Female; Genotype; Genotyping Techniques; HIV; HIV Infections; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Parasite Load; Parasitemia; Plasmodium falciparum; Uganda; Veins; Young Adult

Malaria caused by Plasmodium vivax and Plasmodium falciparum is among the major public health problems in most endemic areas of the world. Artemisinin-based combination therapy (ACT) has been recommended as a first-line treatment for uncomplicated Plasmodium falciparum malaria almost in all endemic regions. Since ineffectively regulated medicines in resource limited settings could favour infiltration of poor quality anti-malarial medicines into pharmaceutical supply chain and jeopardize a positive treatment outcome, regular monitoring of the quality of anti-malarial medicines is critical. Thus, the aim of this study was to assess the quality of fixed dose combination (FDC) artemether (ART)/lumefantrine (LUM) tablets available in Jimma zone, Ethiopia.. This study was conducted in Jimma zone, Ethiopia. A total of 74 samples of FDC ART/LUM (20 mg ART/120 mg LUM) tablets were collected from 27 public facilities. All samples were subjected to visual inspection and the relevant information was recorded. The samples were transported to Jimma University Laboratory of Drug Quality (JuLaDQ) and stored at ambient temperature (20 °C to 25 °C) until analysis. The Pharmacopoeial conform/non-conform methods and the risk-based Derringer's desirability function approach were employed to assess the pharmaceutical quality of the investigated products.. The visual inspection results revealed that there were no signs of falsified in the investigated products. Identification test results of samples indicated that all samples contained the stated active pharmaceutical ingredients (APIs). The results of uniformity of mass indicated that all samples complied with International Pharmacopoeial specification limits. The assay results, expressed as percent label claim (%lc) of ART (89.8 to 108.8%, mean ± SD = 99.1 ± 3.9%) and LUM (90.0 to 111.9%, mean ± SD = 98.2 ± 3.8%) revealed that, all samples complied with International Pharmacopoeia acceptance specification limits (i.e. 90-110%lc), except one generic product (IPCA Laboratories Ltd., India) which contains excessive LUM (111.9 ± 1.7%lc). The risk priority number (RPN) results revealed that assay (RPN = 392) is relatively the most critical quality attribute followed by identity (RPN = 280) and mass uniformity (40). Quality evaluation based on psycho-physical Harrington's scale revealed that more than 96% of samples were within the acceptable ranges (D ≥ 0.7-1.0).. Both Pharmacopoeial and risk-based desirability function approaches to quality evaluation applied to the investigated products revealed that above 96% FDC ART/LUM tablets circulating in public settings of Jimma zone are of good quality.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Ethiopia; Malaria, Falciparum

Molecular characterization of malaria parasites from different localities is important to improve understanding of acquisition of natural immunity to. From 296 distinct fragments detected, 13. Genetic diversity of

Topics: Alleles; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Child, Preschool; Congo; Female; Genetic Variation; Genotype; Humans; Infant; Malaria, Falciparum; Male; Merozoite Surface Protein 1; Plasmodium falciparum; Protozoan Proteins

The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.. At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005.. Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015 (P = 0.002 and P <  0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% CI, 1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P <  0.0001 for each). Enrolment parasitaemia > 75 000 μl. These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.. Pan African Clinical Trial Registration PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015 PACTR201510001189370 , 3 July 2015; PACTR201709002064150 , 1 March 2017; https://www.pactr.samrca.ac.za.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Female; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Plasmodium falciparum

Blackwater fever is a complication of malaria infection consisting of a syndrome of febrile intra-vascular haemolysis with severe anaemia and intermittent passage of dark-red to black colour urine. Despite numerous reports and studies of this condition, its pathogenesis remains incompletely understood.. This report describes a case of classic blackwater fever in a returning traveller, without prior history of malaria infection nor usage of anti-malarial prophylaxis, treated with two courses of oral artemether-lumefantrine combination therapy. Unusual persistence of submicroscopic Plasmodium falciparum parasitaemia was detected by PCR for 18 days after initiation of treatment.. To the authors' knowledge this is the first reported occurrence of a case of blackwater fever associated with prolonged submicroscopic parasitaemia. This unusual case challenges the current knowledge of the pathogenesis of this condition and opens questions that may have important diagnostic and treatment implications.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Blackwater Fever; Communicable Diseases, Imported; Ghana; Humans; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Singapore; Treatment Outcome; Young Adult

Artemisinin-based combination therapy is the first-line anti-malarial treatment for uncomplicated Plasmodium falciparum infection in Angola. To date, the prevalence of polymorphisms in the pfk13 gene, associated with artemisinin resistance, and pfmdr1, associated with lumefantrine resistance, have not been systematically studied in Angola.. DNA was isolated from pretreatment and late treatment failure dried blood spots collected during the 2015 round of therapeutic efficacy studies in Benguela, Lunda Sul, and Zaire Provinces in Angola. The pfk13 propeller domain and pfmdr1 gene were sequenced and analysed for polymorphisms. Pfmdr1 copy number variation was assessed using a real-time PCR method. The association between pfmdr1 and pfk13 mutations and treatment failure was investigated.. The majority of pretreatment (99%, 466/469) and all late treatment failure (100%, 50/50) samples were wild type for pfk13. Three of the pretreatment samples (1%) carried the A578S mutation commonly observed in Africa and not associated with artemisinin resistance. All 543 pretreatment and day of late treatment failure samples successfully analysed for pfmdr1 copy number variation carried one copy of pfmdr1. The NYD haplotype was the predominant pfmdr1 haplotype, present in 63% (308/491) of pretreatment samples, followed by NFD, which was present in 32% (157/491) of pretreatment samples. The pfmdr1 N86 allele was overrepresented in day of late treatment failure samples from participants receiving artemether-lumefantrine (p value 0.03).. The pretreatment parasites in patients participating in therapeutic efficacy studies in 2015 in Angola's three sentinel sites showed genetic evidence of susceptibility to artemisinins, consistent with clinical outcome data showing greater than 99% day 3 clearance rates. The lack of increased pfmdr1 copy number is consistent with previous reports from sub-Saharan Africa. Although pfmdr1 NYD and NFD haplotypes were overrepresented in artemether-lumefantrine late treatment failure samples, their role as markers of resistance was unclear given that these haplotypes were also present in the majority of successfully treated patients in the artemether-lumefantrine treatment arms.

Topics: Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Drug Resistance; Humans; Lumefantrine; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins

Data on prevalence of antimalarial molecular resistance markers in pregnant women in Ghana is scarce. Prevalence of single nucleotide polymorphisms/haplotypes in the

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cross-Sectional Studies; Drug Combinations; Drug Resistance; Female; Genetic Markers; Ghana; Haplotypes; Humans; Infant, Newborn; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Mutation; Plasmodium falciparum; Polymorphism, Single Nucleotide; Pregnancy; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase

The Angolan government recommends three artemisinin-based combinations for the treatment of uncomplicated Plasmodium falciparum malaria: artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Due to the threat of emerging anti-malarial drug resistance, it is important to periodically monitor the efficacy of artemisinin-based combination therapy (ACT). This study evaluated these medications' therapeutic efficacy in Benguela, Lunda Sul, and Zaire Provinces.. Enrollment occurred between March and July 2017. Study participants were children with P. falciparum monoinfection from each provincial capital. Participants received a 3-day course of a quality-assured artemisinin-based combination and were monitored for 28 (AL and ASAQ arms) or 42 days (DP arm). Each ACT was assessed in two provinces. The primary study endpoints were: (1) follow-up without complications and (2) failure to respond to treatment or development of recurrent P. falciparum infection. Parasites from each patient experiencing recurrent infection were genotyped to differentiate new infection from recrudescence of persistent parasitaemia. These parasites were also analysed for molecular markers associated with ACT resistance.. Of 608 children enrolled in the study, 540 (89%) reached a primary study endpoint. Parasitaemia was cleared within 3 days of medication administration in all participants, and no early treatment failures were observed. After exclusion of reinfections, the corrected efficacy of AL was 96% (91-100%, 95% confidence interval) in Zaire and 97% (93-100%) in Lunda Sul. The corrected efficacy of ASAQ was 100% (97-100%) in Benguela and 93% (88-99%) in Zaire. The corrected efficacy of DP was 100% (96-100%) in Benguela and 100% in Lunda Sul. No mutations associated with artemisinin resistance were identified in the pfk13 gene in the 38 cases of recurrent P. falciparum infection. All 33 treatment failures in the AL and ASAQ arms carried pfmdr1 or pfcrt mutations associated with lumefantrine and amodiaquine resistance, respectively, on day of failure.. AL, ASAQ, and DP continue to be efficacious against P. falciparum malaria in these provinces of Angola. Rapid parasite clearance and the absence of genetic evidence of artemisinin resistance are consistent with full susceptibility to artemisinin derivatives. Periodic monitoring of in vivo drug efficacy remains a priority routine activity for Angola.

Topics: Adolescent; Amodiaquine; Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Quinolines; Treatment Failure

Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria.. The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether-lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin-piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration.. Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8-4·4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76-0·88 per quarter) and in other villages (0·75, 0·73-0·78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13-0·26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631).. Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum.. The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Early Diagnosis; Ethanolamines; Female; Fluorenes; Humans; Incidence; Malaria, Falciparum; Male; Mass Drug Administration; Myanmar; Prevalence; Primaquine; Rural Population; State Medicine; Treatment Outcome

PfMDR1 single nucleotide polymorphisms (SNP) are good correlate markers for antimalarial drug resistance worldwide. Present study is a comprehensive view of screening of PfMDR1 polymorphism to antimalarials practiced with geography and time. Study sites Mizoram, Tripura, Meghalaya chosen are at multivariate drug pressure due to cross border migration and transmission. Mizoram is gateway to south east Asia through Myanmar whereas Tripura, Meghalaya share porous border with Bangladesh. Baseline finger pricked blood stained filter paper for confirmed uncomplicated Plasmodium falciparum infected patients (year 2015) were obtained from National Institute of Malaria Research, New Delhi, India. PfMDR1 polymorphism for codon N86Y, Y184F, D1246Y was determined by PCR-RFLP, further confirmed by sequencing. There observed marked predominance of Plasmodium isolates with PfMDR1 wild type alleles for all codons under study i.e. 86, 184, 1246. Spatially, Plasmodium isolates from Mizoram were most diverse with co-existence of PfMDR1 genotype with NYD, YYD, NFD haplotypes, followed by Tripura. Isolates from Meghalaya were of all NYD haplotype. Reports, referring to screening of PfMDR1 SNPs to CQ/SP/AS-SP across India, were archived. Temporal study show distinct rise in proportion of PfMDR1 wild type N86 allele since introduction of Artemether-Lumefantrine as first line antimalarial. Hence spatio-temporal screening of Plasmodium population with PfMDR1 single nucleotide polymorphism accounts for its association with antimalarial susceptibility and validate PfMDR1 SNPs as antimalarial drug resistant marker.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bangladesh; Chloroquine; Drug Combinations; Drug Resistance; Erythrocytes; Gene Expression; Haplotypes; Humans; India; Lumefantrine; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Myanmar; Phylogeny; Phylogeography; Plasmodium falciparum; Polymorphism, Single Nucleotide; Pyrimethamine; Sulfadoxine

The efficacies of 3-day regimens of artemether-lumefantrine (AL), artesunate-amodiaquine (AA), and dihydroartemisinin-piperaquine (DHP) were evaluated in 910 children < 5 years old with uncomplicated malaria from six geographical areas of Nigeria. Parasite positivity 1 day and Kaplan-Meier estimated risk of persistent parasitemia 3 days after therapy initiation were both significantly higher, and geometric mean parasite reduction ratio 1 day after treatment initiation (PRRD1) was significantly lower in AL-treated children than in AA- and DHP-treated children. No history of fever, temperature > 38°C, enrollment parasitemia > 75,000 μL

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Plasmodium falciparum; Quinolines; Treatment Outcome

Malaria burden remains high in the sub-Saharan region where helminths are prevalent and where children are often infected with both types of parasites. Although the effect of helminths on malaria infection is evident, the impact of these co-infections is not clearly elucidated yet and the scarce findings are conflicting. In this study, we investigated the effect of schistosomiasis, considering soil-transmitted helminths (STH), on prevalence and incidence of Plasmodium falciparum infection.. This longitudinal survey was conducted in school-age children living in two rural communities in the vicinity of Lambaréné, Gabon. Thick blood smear light microscopy, urine filtration and the Kato-Katz technique were performed to detect malaria parasites, S. haematobium eggs and, STH eggs, respectively. P. falciparum carriage was assessed at inclusion, and incidence of malaria and time to the first malaria event were recorded in correlation with Schistosoma carriage status. Stratified multivariate analysis using generalized linear model was used to assess the risk of plasmodium infection considering interaction with STH, and survival analysis to assess time to malaria.. The overall prevalence on subject enrolment was 30%, 23% and 9% for S. haematobium, P. falciparum infections and co-infection with both parasites, respectively. Our results showed that schistosomiasis in children tends to increase the risk of plasmodium infection but a combined effect with Trichuris trichiura or hookworm infection clearly increase the risk (aOR = 3.9 [95%CI: 1.7-9.2]). The incidence of malaria over time was 0.51[95%CI: 0.45-0.57] per person-year and was higher in the Schistosoma-infected group compared to the non-infected group (0.61 vs 0.43, p = 0.02), with a significant delay of time-to first-malaria event only in children aged from 6 to 10-years-old infected with Schistosoma haematobium.. Our results suggest that STH enhance the risk for P. falciparum infection in schistosomiasis-positive children, and when infected, that schistosomiasis enhances susceptibility to developing malaria in young children but not in older children.

Topics: Albendazole; Animals; Anthelmintics; Antimalarials; Artemether, Lumefantrine Drug Combination; Child; Female; Gabon; Helminthiasis; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Praziquantel; Risk Factors; Schistosoma haematobium; Schistosomiasis haematobia

Artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization.. Open-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated.. Of the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2-98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1-99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1-100), 100% in Nagaga (n = 39; 95% CI 91.0-100) and Kyela 2015 (n = 60; 95% CI 94.0-100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4-99.9) and 100% (n = 25; 95% CI 86.3-100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9-100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure.. All the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation. Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Prospective Studies; Quinolines; Tanzania

There are concerns that resistance to artemisinin-based combination therapy might emerge in Kenya and sub-Saharan Africa (SSA) in the same pattern as was with chloroquine and sulfadoxine-pyrimethamine. Single nucleotide polymorphisms (SNPs) in critical alleles of pfmdr1 gene have been associated with resistance to artemisinin and its partner drugs. Microsatellite analysis of loci flanking genes associated with anti-malarial drug resistance has been used in defining the geographic origins, dissemination of resistant parasites and identifying regions in the genome that have been under selection.. This study set out to investigate evidence of selective sweep and genetic lineages in pfmdr1 genotypes associated with the use of artemether-lumefantrine (AL), as the first-line treatment in Kenya. Parasites (n = 252) from different regions in Kenya were assayed for SNPs at codons 86, 184 and 1246 and typed for 7 neutral microsatellites and 13 microsatellites loci flanking (± 99 kb) pfmdr1 in Plasmodium falciparum infections.. The data showed differential site and region specific prevalence of SNPs associated with drug resistance in the pfmdr1 gene. The prevalence of pfmdr1 N86, 184F, and D1246 in western Kenya (Kisumu, Kericho and Kisii) compared to the coast of Kenya (Malindi) was 92.9% vs. 66.7%, 53.5% vs. to 24.2% and 96% vs. to 87.9%, respectively. The NFD haplotype which is consistent with AL selection was at 51% in western Kenya compared to 25% in coastal Kenya.. Selection pressures were observed to be different in different regions of Kenya, especially the western region compared to the coastal region. The data showed independent genetic lineages for all the pfmdr1 alleles. The evidence of soft sweeps in pfmdr1 observed varied in direction from one region to another. This is challenging for malaria control programs in SSA which clearly indicate effective malaria control policies should be based on the region and not at a country wide level.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Drug Resistance; Kenya; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Selection, Genetic

The resistance of Plasmodium falciparum to anti-malarial drugs continues to challenge malaria control. We assessed the therapeutic efficacy and safety of artemether-lumefantrine (AL), the first-line treatment of uncomplicated P. falciparum malaria, in children under five years of age in Mozambique. We conducted a prospective one-arm study to evaluate the clinical and parasitological efficacy of AL over 28days at four sentinel sites, using the WHO protocol for assessing the efficacy of antimalarial treatment. msp1, msp2 and glurp genes were analysed by DNA polymerase chain reaction (PCR) to differentiate recrudescence from re-infection with malaria parasites. Haemoglobin concentration was recorded at baseline and on days 7, 14 and 28. A total of 349 children with uncomplicated falciparum malaria were recruited at the four sentinel sites. Adequate clinical and parasitological response to AL on day 28 follow-up varied from 96.3% to 100% after correction by PCR. The drug was well tolerated, and no adverse event related to the drug was reported. AL, the current first-line treatment for uncomplicated falciparum malaria in Mozambique, remains highly efficacious at the study sites. Monitoring of the efficacy of the recommended antimalarial drugs should be continued in order to detect any emerging threat to their efficacy.. ACTRN12616001680459.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mozambique; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Recurrence

In severe malaria, intravenous artesunate may cause delayed haemolytic anaemia but there has been little evaluation of the propensity of oral artemisinin-based combination treatments (ACTs) to cause late-appearing anaemia.. The frequency of anaemia (haematocrit <30%), and temporal changes in haematocrit were evaluated in 1,191 malarious children following ACTs. "Haematocrit conservation" was evaluated by using the fall in haematocrit/1,000 asexual parasites cleared from the peripheral blood (FIH/1,000 asexual parasites cpb), and the ratio of the average haematocrit (on the first 3 days of starting treatment):total parasitaemia cleared.. The frequency of anaemia decreased significantly following treatment. FIH/1,000 asexual parasites cpb, average haematocrit:total parasitaemia cleared, and mean haematocrit 5 weeks after treatment began were significantly lower in hyperparasitaemic children than in children without hyperparasitaemia, suggesting haematocrit conservation during treatment followed later by a loss of haematocrit. Asymptomatic late-appearing anaemia occurred in 6% of the children.. Artesunate-amodiaquine and artemether-lumefantrine contribute to haematocrit conservation at high parasitaemias but may cause late-appearing anaemia.

Topics: Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Hematocrit; Humans; Infant; Malaria, Falciparum; Male; Parasitemia

Artemisinin combination therapy is first-line therapy for treatment of malaria, which is one of the most significant public health problems in Nigeria. With the increasing level of use of these drugs coupled with the emergence of resistance, there is a need for regular post-market surveillance.. Twenty different brands of artesunate-containing antimalarial drugs and 10 brands of artemether-lumefantrine were multi-sourced in the south western part of Nigeria and were subjected to identification, weight uniformity test, and assay using United State pharmacopoeia and International Pharmacopoeia monographs. In vitro-dissolution test of the artemether tablets was also investigated.. All 10 brands (100%) of the artemether-lumefantrine tablets met the assay requirement for artemether and 8 (80%) met the assay requirement for lumefantrine, but only 4 brands (40%) met the requirement for artemether dissolution. One of these brands failed the weight uniformity test. Of the 20 brands of artesunate-containing brands included in this study, 15 (75%) met the standard assay requirement for artesunate and two failed the weight uniformity test.. There is evidence of the presence of substandard artemisinin products in the Nigerian market.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Drug and Narcotic Control; Drug Combinations; Drug Evaluation; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Nigeria; Quality Control

Plasmodium falciparum may cause serious and sometimes even fatal cerebral malaria. Cerebral malaria is a disease characterized by alterations in consciousness and epileptic attacks; therefore, it requires a rapid evaluation and quick intervention. It may progress to a fatal outcome despite administering targeted therapeutic interventions. There are studies indicating that erythrocyte exchange (erythrocytapheresis) can be a treatment modality for managing severe malaria patients. In this case report, the successful management of a cerebral malaria patient by the combination of antimalarial drug therapy and erythrocyte exchange is presented.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Erythrocyte Transfusion; Ethanolamines; Fluorenes; Humans; Malaria, Cerebral; Malaria, Falciparum; Male; Plasmodium falciparum

Topics: Adolescent; Adult; Artemether, Lumefantrine Drug Combination; Artemisinins; Colombia; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Germ Cells; Humans; Malaria, Falciparum; Male; Middle Aged; Primaquine; Young Adult

A recent randomized trial showed that artemisinin-naphthoquine (AN) was non-inferior to artemether-lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens.. An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen's incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved.. In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5-5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL.. Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cost-Benefit Analysis; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Randomized Controlled Trials as Topic; Treatment Outcome

Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub-optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates the data on the human immune response to the parasite, and AL's pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Host-Parasite Interactions; Humans; Malaria, Falciparum; Models, Biological; Patient Compliance; Tanzania; Treatment Outcome

Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether-lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults.. A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures.. Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases.. Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genotype; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Retrospective Studies; Risk Factors; Severity of Illness Index; Sweden; Travel; Treatment Failure; Treatment Outcome; Young Adult

Individual drug treatment may select resistant parasites in the human body, a process termed in vivo selection. Some single nucleotide polymorphisms in Plasmodium falciparum chloroquine-resistance transporter (pfcrt) and multidrug resistance gene 1 (pfmdr1) genes have been reportedly selected after artemether-lumefantrine treatment. However, there is a paucity of data regarding in vivo selection of P. falciparum Kelch propeller domain (pfkelch13) polymorphisms, responsible for artemisinin-resistance in Asia, and six putative background mutations for artemisinin resistance; D193Y in ferredoxin, T484I in multiple resistance protein 2, V127M in apicoplast ribosomal protein S10, I356T in pfcrt, V1157L in protein phosphatase and C1484F in phosphoinositide-binding protein.. Artemether-lumefantrine efficacy study with a follow-up period of 28 days was conducted in northern Uganda in 2014. The above-mentioned genotypes were comparatively analysed before drug administration and on days; 3, 7, and 28 days after treatment.. In 61 individuals with successful follow-up, artemether-lumefantrine treatment regimen was very effective with PCR adjusted efficacy of 95.2%. Among 146 isolates obtained before treatment, wild-type alleles were observed in 98.6% of isolates in pfkelch13 and in all isolates in the six putative background genes except I356T in pfcrt, which had 2.4% of isolates as mixed infections. In vivo selection study revealed that all isolates detected in the follow-up period harboured wild type alleles in pfkelch13 and the six background genes.. Mutations in pfkelch13 and the six background genes may not play an important role in the in vivo selection after artemether-lumefantrine treatment in Uganda. Different mechanisms might rather be associated with the existence of parasites after treatment.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Selection, Genetic; Uganda; Young Adult

Artemisinin-based therapy is the current standard treatment for non-severe malaria due to Plasmodium falciparum. The potential for asymptomatic liver toxicity of this therapy and its implication in clinical practice is currently unknown. The aim of this study is to assess the hepatic function in patients treated with a standard three-day artemisinin-based regimen and to compare it with the quinine-doxycycline regimen.. Retrospective and comparative study of returned adult travellers admitted with non-severe P. falciparum malaria. Fifty-seven patients were included: 19 treated with artemisinin-based therapy and 38 with quinine-doxycycline therapy.. During treatment, when compared with quinine-doxycycline group, the artemisinin-lumefantrine group presented a higher proportion of significant liver enzyme abnormalities (42 vs. 5%, p < 0.01) and a higher peak value of aspartate aminotransferase (131 vs. 64 U/L, p < 0.01) and alanine aminotransferase (99 vs. 75 U/L, p = 0.05). None of the patients was symptomatic, there were no treatment interruptions and all patients achieved clinical cure.. Treatment of uncomplicated falciparum malaria with artemisinin-based therapy might cause asymptomatic liver enzyme abnormalities in the first days of treatment. Nevertheless, these liver enzyme abnormalities seem to be harmless, asymptomatic and self-limited.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cohort Studies; Doxycycline; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Malaria; Malaria, Falciparum; Male; Middle Aged; Portugal; Quinine; Retrospective Studies

We present case histories of four patients treated with artemether-lumefantrine for falciparum malaria in UK hospitals in 2015 to 2016. Each subsequently presented with recurrent symptoms and

Topics: Africa; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Gene Expression; Genetic Loci; Humans; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Recurrence; Travel; Treatment Failure; United Kingdom; Young Adult

Artemisinin-based combination therapy is the recommended first-line treatment for uncomplicated falciparum malaria worldwide. However, recent studies conducted in Mali showed an increased frequency of recurrent parasitaemia following artemether-lumefantrine (AL) treatment.. Study samples were collected during a large WANECAM study. Ex-vivo Plasmodium falciparum sensitivity to artemether and lumefantrine was assessed using the tritiated hypoxanthine-based assay. The prevalence of molecular markers of anti-malarial drug resistance (pfcrt K76T, pfmdr1 N86Y and K13-propeller) were measured by PCR and/or sequencing.. Overall 61 samples were successfully analysed in ex vivo studies. Mean IC. Malian post-AL P. falciparum isolates were less susceptible to artemether and lumefantrine than baseline isolates.

Topics: Administration, Oral; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Mali; Parasitemia; Plasmodium falciparum; Recurrence

Recent anti-malarial resistance monitoring in Angola has shown efficacy of artemether-lumefantrine (AL) in certain sites approaching the key 90% lower limit of efficacy recommended for artemisinin-based combination therapy. In addition, a controversial case of malaria unresponsive to artemisinins was reported in a patient infected in Lunda Sul Province in 2013.. During January-June 2015, investigators monitored the clinical and parasitological response of children with uncomplicated Plasmodium falciparum infection treated with AL, artesunate-amodiaquine (ASAQ), or dihydroartemisinin-piperaquine (DP). The study comprised two treatment arms in each of three provinces: Benguela (AL, ASAQ), Zaire (AL, DP), and Lunda Sul (ASAQ, DP). Samples from treatment failures were analysed for molecular markers of resistance for artemisinin (K13) and lumefantrine (pfmdr1).. A total of 467 children reached a study endpoint. Fifty-four treatment failures were observed: four early treatment failures, 40 re-infections and ten recrudescences. Excluding re-infections, the 28-day microsatellite-corrected efficacy was 96.3% (95% CI 91-100) for AL in Benguela, 99.9% (95-100) for ASAQ in Benguela, 88.1% (81-95) for AL in Zaire, and 100% for ASAQ in Lunda Sul. For DP, the 42-day corrected efficacy was 98.8% (96-100) in Zaire and 100% in Lunda Sul. All treatment failures were wild type for K13, but all AL treatment failures had pfmdr1 haplotypes associated with decreased lumefantrine susceptibility.. No evidence was found to corroborate the specific allegation of artemisinin resistance in Lunda Sul. The efficacy below 90% of AL in Zaire matches findings from 2013 from the same site. Further monitoring, particularly including measurement of lumefantrine blood levels, is recommended.

Topics: Amodiaquine; Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Quinolines; Recurrence; Treatment Failure

Artemisinin-based combination treatments (ACTs) are the first-line treatments of uncomplicated Plasmodium falciparum malaria in many endemic areas but there are few evaluation of their efficacy in anaemic malarious children.. Therapeutic efficacy of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine was evaluated in 437 anaemic and 909 non-anaemic malarious children following treatment during a seven-year period (2008-2014). Patterns of temporal changes in haematocrit were classified based on haematocrit values <30% and ≥30%. Kinetics of the disposition of the deficit in haematocrit from 30% following treatment were evaluated using a non-compartment model.. PCR-corrected parasitological efficacy 28 days after start of treatment was significantly higher in artesunate-amodiaquine- compared to artemether-lumefantrine-treated children [97% (95%CI: 92.8-100) versus 96.4% (95%CI: 91.3-99.4), P = 0.02], but it was similar in non-anaemic and anaemic children. Fall in haematocrit/1 000 asexual parasites cleared from peripheral blood was significantly greater at lower compared to higher parasitaemias (P < 0.0001), and in non-anaemic compared to anaemic children (P = 0.007). In anaemic children at presentation, mean anaemia recovery time (AnRT) was 15.4 days (95%CI: 13.3-17.4) and it did not change over the years. Declines in haematocrit deficits from 30% were monoexponential with mean estimated half-time of 1.4 days (95%CI: 1.2-1.6). Anaemia half-time (t. Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated P. falciparum infections in non-anaemic and anaemic Nigerian children in the last 7 years of adoption as first-line treatments. These ACTs may also conserve haematocrit at high parasitaemias and in anaemic children.. Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015.

Topics: Adolescent; Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Hematocrit; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Treatment Outcome

AbstractRecently, reports of delayed hemolytic anemia after treatment with artemisinin and its derivatives have emerged. Here we report two cases of delayed hemolytic anemia in a patient with severe falciparum malaria after treatment with oral artemether-lumefantrine (AL). The first patient, a 20-year-old Japanese male student, was diagnosed with falciparum malaria and was administered AL. As having a high parasitemia rate (20.6%) was the only severe malaria criterion met in this case and his general condition was stable, we continued with AL treatment. Despite disappearance of malarial parasites after 4 days of AL administration, a persistent fever remained. On days 13 and 16, a diagnosis of hemolytic anemia was made (lactate dehydrogenase [LDH]: 1,466 U/L, hemoglobin [Hb]: 7.2 g/dL). A blood smear at that time revealed no parasites. He recovered naturally from delayed hemolysis. The second patient, a 27-year-old Japanese female student, was diagnosed with falciparum malaria (parasitemia: 4.5%) and treated initially with oral quinine hydrochloride and doxycycline. The following day, parasitemia increased to 7.9% and oral AL was initiated. She was discharged on day 4 after achieving parasite clearance and afebrility. However, on day 5, fever (body temperature > 38°C) recurred, and on day 11, a diagnosis of hemolytic anemia was made (LDH: 712 U/L, Hb: 8.8 g/dL). A follow-up confirmed that her condition improved gradually. AL treatment of severe malaria can cause delayed hemolytic anemia. Patients should be followed up for up to 4 weeks to detect signs of hemolysis and provide appropriate symptomatic treatment.

Topics: Adult; Anemia, Hemolytic; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Blood Cell Count; Convalescence; Drug Combinations; Ethanolamines; Female; Fluorenes; Hemoglobins; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Time Factors

Artemisinin combination therapy (ACT) is the first line to treat uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin treatment failures are on the rise in southeast Asia. Delayed parasite clearance after ACT is associated with mutations of the P. falciparum kelch 13 gene. Patients (N = 148) in five districts of northwest Ethiopia were enrolled in a 28-day ACT trial. We identified a unique kelch 13 mutation (R622I) in 3/125 (2.4%) samples. The three isolates with R622I were from Negade-Bahir and Aykel districts close to the Ethiopia-Sudan border. One of three patients with the mutant strain was parasitemic at day 3; however, all patients cleared parasites by day 28. Correlation between kelch 13 mutations and parasite clearance was not possible due to the low frequency of mutations in this study.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Gene Expression Regulation; Humans; Infant; Malaria, Falciparum; Middle Aged; Mutation; Plasmodium falciparum; Protozoan Proteins; Young Adult

Although artemisinin resistance has yet to be reported in Africa, surveillance of the efficacy of artemisinin-based combination therapies (ACTs) is warranted. Here, the efficacy of artesunate + sulfadoxine-pyrimethamine (AS + SP) and artemether-lumefantrine (AL) was evaluated in Mali. Randomized open-label comparative in vivo assay of AS + SP versus AL were carried out using the 28-day follow-up World Health Organization protocol. Patients with uncomplicated falciparum malaria and at least 6 months of age were recruited between October 2010 and January 2014. A subset of these patients was selected to measure Plasmodium falciparum clearance time. Polymerase chain reaction-corrected adequate clinical and parasitological responses were 100% for AS + SP and 98.2% for AL with no significant difference (P = 0.06). The reinfection rates were comparable (P = 0.63) with 8.0% for AS + SP and 12.6% for AL. Individuals under 8 years were more susceptible to treatment failure (relative risk = 1.9; 95% confidence interval = 1.2, 3.3). Median parasite clearance half-life was 1.7 hours (interquartile range [IQR] = 1.3-2.2) for AS + SP and 1.9 hours (IQR = 1.5-2.5) for AL with no statistically significant difference (P = 0.24). Efficacy of AS + SP and AL was high. This study provides baseline information on parasite clearance half-lives after ACT treatment, particularly AS + SP, in Mali.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Mali; Plasmodium falciparum; Pyrimethamine; Sulfadoxine

Artemisinin-based combination therapy has been first-line treatment for falciparum malaria in Myanmar since 2005. The wide extent of artemisinin resistance in the Greater Mekong sub-region and the presence of mefloquine resistance at the Myanmar-Thailand border raise concerns over resistance patterns in Myanmar. The availability of molecular markers for resistance to both drugs enables assessment even in remote malaria-endemic areas.. A total of 250 dried blood spot samples collected from patients with Plasmodium falciparum malarial infection in five malaria-endemic areas across Myanmar were analysed for kelch 13 sequence (k13) and pfmdr1 copy number variation. K13 mutations in the region corresponding to amino acids 210-726 (including the propeller region of the protein) were detected by nested PCR amplification and sequencing, and pfmdr1 copy number variation by real-time PCR. In two sites, a sub-set of patients were prospectively followed up for assessment of day-3 parasite clearance rates after a standard course of artemether-lumefantrine.. K13 mutations and pfmdr1 amplification were successfully analysed in 206 and 218 samples, respectively. Sixty-nine isolates (33.5 %) had mutations within the k13 propeller region with 53 of these (76.8 %) having mutations already known to be associated with artemisinin resistance. F446I (32 isolates) and P574L (15 isolates) were the most common examples. K13 mutation was less common in sites in western border regions (29 of 155 isolates) compared to samples from the east and north (40 of 51 isolates; p < 0.0001). The overall proportion of parasites with multiple pfmdr1 copies (greater than 1.5) was 5.5 %. Seven samples showed both k13 mutation and multiple copies of pfmdr1. Only one of 36 patients followed up after artemether-lumefantrine treatment still had parasites at day 3; molecular analysis indicated wild-type k13 and single copy pfmdr1.. The proportion of P. falciparum isolates with mutations in the propeller region of k13 indicates that artemisinin resistance extends across much of Myanmar. There is a low prevalence of parasites with multiple pfmdr1 copies across the country. The efficacy of artemisinin-based combination therapy containing mefloquine and lumefantrine is, therefore, expected to be high, although regular monitoring of efficacy will be important.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; DNA Copy Number Variations; DNA, Protozoan; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Mutation; Myanmar; Plasmodium falciparum; Prospective Studies

The adoption of Artemisinin based combination therapies (ACT) constitutes a basic strategy for malaria control in sub-Saharan Africa. Moreover, since cases of ACT resistance have been reported in South-East Asia, the need to understand P. falciparum resistance mechanism to ACT has become a global research goal. The selective pressure of ACT and the possibility that some specific Pfcrt and Pfmdr1 alleles are associated with treatment failures was assessed in a clinical trial comparing ASAQ to AL in Nanoro. Dried blood spots collected on Day 0 and on the day of recurrent parasitaemia during the 28-day follow-up were analyzed using the restriction fragments length polymorphism (PCR-RFLP) method to detect single nucleotide polymorphisms (SNPs) in Pfcrt (codon76) and Pfmdr1 (codons 86, 184, 1034, 1042, and 1246) genes. Multivariate analysis of the relationship between the presence of Pfcrt and Pfmdr1 alleles and treatment outcome was performed. AL and ASAQ exerted opposite trends in selecting Pfcrt K76T and Pfmdr1-N86Y alleles, raising the potential beneficial effect of using diverse ACT at the same time as first line treatments to reduce the selective pressure by each treatment regimen. No clear association between the presence of Pfcrt and Pfmdr1 alleles carried at baseline and treatment failure was observed.

Topics: Adult; Aged; Alleles; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Drug Combinations; Ethanolamines; Female; Fluorenes; Gene Frequency; Genotype; Host-Parasite Interactions; Humans; Malaria, Falciparum; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Proteins; Multivariate Analysis; Parasitemia; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Treatment Outcome

As per the WHO recommendation, the development of resistance by P. falciparum to most artemisinin combination therapies (ACTs) triggered the need for routine monitoring of the efficacy of the drugs every two years in all malaria endemic countries. Hence, this study was carried out to assess the therapeutic efficacy of Artemether-Lumefantrine (Coartem®) in treating the uncomplicated falciparum malaria, after 9 years of its introduction in the Metehara, Eastern Ethiopia.. This is part of the therapeutic efficacy studies by the Federal Ministry of Health Ethiopia, which were conducted in regionally representative sentinel sites in the country from October 2014 to January 2015. Based on the study criteria set by WHO, febrile and malaria suspected outpatients in the health center were consecutively recruited to study. A standard six-dose regimen of AL was administered over three days and followed up for measuring therapeutic responses over 28 days. Data entry and analysis was done by using the WHO designed Excel spreadsheet and SPSS version 20 for Windows. Statistical significant was considered for P-value less than 0.05.. Of the 91 patients enrolled, the day-28 analysis showed 83 adequate clinical and parasitological responses (ACPRs). Per protocol analysis, PCR-uncorrected & corrected cure rates of Coartem® among the study participants were 97.6% (95%CI: 93.6-99.5) and 98.8% (CI: 93.5-100%), respectively. No parasite detected on day 3 and onwards. Fever clearance was above 91% on day-3. Mean hemoglobin was significantly increased (P<0.000) from 12.39 g/dl at day 0 to 13.45 g/dl on day 28. No serious adverse drug reactions were observed among the study participants.. This study showed high efficacy of AL in the study area, which suggests the continuation of AL as first line drug for the treatment of uncomplicated P. falciparum malaria in the study area. This study recommends further studies on drug toxicity, particularly on repeated cough and oral ulceration.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Ethiopia; Female; Fluorenes; Hemoglobins; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Treatment Outcome

The optimal treatment of malaria in human immunodeficiency virus (HIV)-infected children requires consideration of critical drug-drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes.. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated.. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART.. The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted.

Topics: Anti-Retroviral Agents; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Coinfection; Drug Combinations; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Infant; Malaria; Malaria, Falciparum; Male; Prospective Studies; Treatment Outcome; Uganda

Among Plasmodium species the causative agent of malaria in Turkey is P.vivax, however the incidence of imported falciparum malaria cases is steadily increasing. P.falciparum may cause severe malaria with the involvement of central nervous system, acute renal failure, severe anemia or acute respiratory distress syndrome. Furhermore most of the casualties due to malaria are related with P.falciparum. There is recently, a considerable increase in malaria infections especially in tropical areas. In this report, three cases, who have admitted to our hospital with three different clinical presentations of falciparum malaria, and all shared common history of travelling to Africa were presented. First case was a 27 years old, male patient who returned from Malawi seven days ago where he stayed for two weeks. He admitted to our hospital with the complaints of sensation of cold, shivering and fever. In physical examination his body temperature was 37.9°C, C-reactive protein level was high, and the other systemic results were normal. The second case was a 25 years old, male patient who returned from Gambia two weeks ago. He was suffering from fever, headache, shivering and unable to maintain his balance. The patient's body temperature was 38°C. Laboratory tests revealed hyperbilirubinemia and thrombocytopenia. Parasitological examination of the Giemsa-stained peripheral blood smear of these two patients demonstrated ring forms compatible with P.falciparum. Treatment was commenced with arthemeter plus lumefantrine, resulting with complete cure. Third case was a 46 years old, male patient who had been working in Uganda, and returned to Turkey two weeks ago. He had sudden onset of fever, headache, nausea and vomiting and impaired consciousness. His peripheral blood smear revealed ring-formed trophozoites and banana-shaped gametocytes of P.falciparum. Arthemeter plus lumefantrine therapy was started, however, he developed severe thrombocytopenia and jaundice under treatment. His general condition was detoriated and the patient lost his consciousness. As the patient's clinical signs were compatible with sepsis ceftriaxone plus clindamycin were added to the antiparasitic treatment emprically. Due to the development of acute tubular necrosis, the patient have undergone hemodialysis. On the 9th day of therapy the complaints and laboratory findings of the patient have improved, so he was discharged. However, visual defects due to retinopathy and severe neurocognitive impairm

Topics: Adult; Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Ceftriaxone; Clindamycin; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Travel; Turkey

Day 7 plasma concentrations of lumefantrine (LF) can serve as a marker to predict malaria treatment outcome in different study populations. Two main cut-off points (175 and 280 ng/ml) are used to indicate plasma concentrations of LF, below which treatment failure is anticipated. However, there is limited data on the cumulative risk of recurrent parasitaemia (RP) in relation to day 7 LF plasma concentrations in pregnant women. This study describes the prevalence, severity, factors influencing treatment outcome of malaria in pregnancy and day 7 LF plasma concentration therapeutic cut-off points that predicts treatment outcome in pregnant women.. This was a one-arm prospective cohort study whereby 89 pregnant women with uncomplicated Plasmodium falciparum malaria receiving artemether-lumefantrine (ALu) participated in pharmacokinetics and pharmacodynamics study. Blood samples were collected on days 0, 2, 7, 14, 21 and 28 for malaria parasite quantification. LF plasma concentrations were determined on day 7. The primary outcome measure was an adequate clinical and parasitological response (ACPR) after treatment with ALu.. The prevalence of malaria in pregnant women was 8.1 % (95 % CI 6.85-9.35) of whom 3.4 % (95 % CI 1.49-8.51) had severe malaria. The overall PCR-uncorrected treatment failure rate was 11.7 % (95 % CI 0.54-13.46 %). Low baseline hemoglobin (<10 g/dl) and day 7 LF concentration <600 ng/ml were significant predictors of RP. The median day 7 LF concentration was significantly lower in pregnant women with RP (270 ng/ml) than those with ACPR (705 ng/ml) (p = 0.016). The relative risk of RP was 4.8 folds higher (p = 0.034) when cut-off of <280 ng/ml was compared to ≥280 ng/ml and 7.8-folds higher (p = 0.022) when cut-off of <600 ng/ml was compared to ≥600 ng/ml. The cut-off value of 175 ng/ml was not associated with the risk of RP (p = 0.399).. Pregnant women with day 7 LF concentration <600 ng/ml are at high risk of RP than those with ≥600 ng/ml. To achieve effective therapeutic outcome, higher day 7 venous plasma LF concentration ≥600 ng/ml is required for pregnant patients than the previously suggested cut-off value of 175 or 280 ng/ml for non-pregnant adult patients.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Plasma; Pregnancy; Pregnancy Complications, Infectious; Prevalence; Prospective Studies; Recurrence; Secondary Prevention; Treatment Outcome; Young Adult

The present paper reports on studies that evaluated artesunate + sulfadoxine-pyrimethamine (AS + SP) which is the first-line drug and artemether-lumefantrine (AL) which is a second-line drug against uncomplicated falciparum malaria in Sudan. This evaluation was performed in twenty studies covering six sentinel sites during five successive annual malaria transmission seasons from 2010 to 2015.. The standard World Health Organization protocol was used for a follow-up period of 28 days. The frequency distribution of molecular markers for antifolate resistance in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes was studied in pre-treatment samples in four sites in 2011.. In the nine studies of AL conducted at five sites (n = 595), high PCR-corrected cure rates were found, ranging from 96.8 to 100 %. Among the eleven studies of AS + SP (n = 1013), a decline in the PCR-corrected cure rates was observed in Gedaref in Eastern Sudan: 91.0 % in the 2011-12 season and 86.5 % in the 2014-15 season. In the remaining sites, the AS + SP cure rates ranged between 95.6 and 100 %. The rate of clearance of microscopic gametocytaemia after treatment was not significantly different with AL or AS + SP on days 7, 14, 21 and 28 of follow-up. A total of 371 pre-treatment samples were analysed for molecular markers of SP resistance. The temporal changes and geographical differences in the frequency distribution of SP-resistance genotypes showed evidence of regional differentiation and selection of resistant strains.. The findings of this study call for a need to review the Sudan malaria treatment policy. Epidemiological factors could play a major role in the emergence of drug-resistant malaria in eastern Sudan.. Trial registration numbers 2011-2012: ACTRN12611001253998, 2013-2015: ACTRN12613000945729.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genetic Markers; Genotype; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Pyrimethamine; Sudan; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Treatment Outcome; Young Adult

In areas with ongoing malaria transmission, strategies to clear parasites from populations can reduce infection and transmission. The objective of this paper was to describe a malaria mass testing and treatment (MTAT) intervention implemented in six kebeles (villages) in Amhara Region, Ethiopia, at the beginning of the 2014 transmission season.. Intervention kebeles were selected based on incidence of passively detected Plasmodium falciparum and mixed (P. falciparum and P. vivax) malaria cases during the 2013 malaria transmission season. All households in intervention kebeles were targeted; consenting residents received a rapid diagnostic test (RDT) and RDT-positive individuals received artemether-lumefantrine for P. falciparum/mixed infections or chloroquine for P. vivax. Data were collected on MTAT participation, sociodemographic characteristics, malaria risk factors, and RDT positivity.. Of 9162 households targeted, 7974 (87.0 %) participated in the MTAT. Among the 35,389 residents of these households, 30,712 (86.8 %) received an RDT. RDT-positivity was 1.4 % (0.3 % P. vivax, 0.7 % P. falciparum, 0.3 % mixed), ranging from 0.3 to 5.1 % by kebele; 39.4 % of RDT-positive individuals were febrile, 28.5 % resided in the same household with another RDT-positive individual, 23.0 % were not protected by vector control interventions [mosquito net or indoor residual spray (IRS)], and 7.1 % had travel history. For individuals under 10 years of age, the odds of being RDT-positive was significantly higher for those with fever, recent use of anti-malarial drugs or residing in the same household with another RDT-positive individual; 59.0 % of RDT-positive individuals had at least one of these risk factors. For individuals 10 years of age and older, the odds of being RDT positive was significantly higher for those with reported travel, fever, recent use of anti-malarial drugs, no use of vector control, and those residing in the same household as another RDT-positive individual; 71.2 % of RDT-positive individuals had at least one of these risk factors.. In the Ethiopia setting, an MTAT intervention is operationally feasible and can be conducted with high coverage. RDT-positivity is low and varies widely by kebele. While several risk factors are significantly associated with RDT-positivity, there are still many RDT-positive individuals who do not have any of these risk factors. Strategies that target populations for testing and treatment based on these risk factors alone are likely to leave many infections undetected.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Coinfection; Drug Combinations; Drug Therapy; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Rural Population; Surveys and Questionnaires; Young Adult

Since 2005, the Togo National Malaria Control Programme has recommended two different formulations of artemisinin-based combination therapy (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL), for the treatment of uncomplicated malaria. Regular efficacy monitoring of these two combinations is conducted every 2 or 3 years. This paper reports the latest efficacy assessment results and the investigation of mutations in the k13 propeller domain.. The study was conducted in 2012-2013 on three sentinel sites of Togo (Lomé, Sokodé and Niamtougou). Children aged 6-59 months, who were symptomatically infected with Plasmodium falciparum, were treated with either AL (Coartem(®), Novartis Pharma, Switzerland) or ASAQ (Co-Arsucam(®), Sanofi Aventis, France). The WHO standard protocol for anti-malarial treatment evaluation was used. The primary end-point was 28-day adequate clinical and parasitological response (ACPR), corrected to exclude reinfection using polymerase-chain reaction (PCR) genotyping.. A total of 523 children were included in the study. PCR-corrected ACPR was 96.3-100 % for ASAQ and 97-100 % for AL across the three study sites. Adverse events were negligible: 0-4.8 % across all sites, for both artemisinin-based combinations. Upon investigation of mutations in the k13 propeller domain, only 9 (1.8 %) mutations were reported, three in each site. All mutant parasites were cleared before day 3. All day 3 positive patients were infected with k13 wild type parasites.. The efficacy of AL and ASAQ remains high in Togo, and both drugs are well tolerated. ASAQ and AL would be recommended for the treatment of uncomplicated malaria in Togo.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genotyping Techniques; Humans; Infant; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Protozoan Proteins; Togo; Treatment Outcome

Artemisinin-based combination therapies are recommended as first-line treatments for uncomplicated falciparum malaria, but there is little evaluation of their efficacy and effects on uncomplicated malaria-associated anaemia in children aged 2 years and under.. Parasitological efficacy and effects on malaria-associated anaemia were evaluated in 250 malarious children aged 2 years and under, and efficacy was evaluated in 603 malarious children older than two but younger than 5 years of age following treatment with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL). Kinetics of the disposition of parasitaemia following treatment were evaluated using a non-compartment model. Late-appearing anaemia (LAA) was diagnosed using the following criteria: clearance of parasitaemia, fever and other symptoms occurring within 7 days of starting treatment, adequate clinical and parasitological response on days 28-42, haematocrit (HCT) ≥ 30 % at 1 and/or 2 weeks, a fall in HCT to < 30 % occurring at 3-6 weeks, absence of concomitant illness at 1-6 weeks, and absence of asexual parasitaemia detected using both microscopy and polymerase chain reaction (PCR) at 1-6 weeks.. Overall, in children aged 2 years and under, the PCR-corrected parasitological efficacy was 97.2 % (95 % CI 92.8-101.6), which was similar for both treatments. In children older than 2 years, parasitological efficacy was also similar for both treatments, but parasite prevalence 1 day after treatment began was significantly higher, and fever and parasite clearance times were significantly faster in the AA-treated children compared with the AL-treated children. Declines in parasitaemia were monoexponential with an estimated elimination half-time of 1 h. Elimination half-times were similar for both treatments. In children aged 2 years and under who were anaemic at presentation, the mean anaemia recovery time was 12.1 days (95 % CI 10.6-13.6, n = 127), which was similar for both treatments. Relatively asymptomatic LAA occurred in 11 children (4.4 %) aged 2 years and under, the recovery from which was uneventful.. This study showed that AA and AL are efficacious treatments for uncomplicated falciparum malaria in Nigerian children aged 2 years and under, and that AA clears parasitaemia and fever significantly faster than AL in children older than 2 years. Both treatments may cause a relatively asymptomatic LAA with uneventful recovery in a small proportion of children aged 2 years and under.. Pan African Clinical Trial Registry PACTR201508001188143, 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015  http://www.pactr.org .

Topics: Amodiaquine; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Treatment Outcome

In Benin, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment for uncomplicated Plasmodium falciparum malaria since 2004. The emergence in Southeast Asia of parasites that are resistant to artemisinins poses a serious threat to global control of this disease. The presence of artemisinin resistance genotypes in parasite populations in Benin is currently unknown. The present study investigated the prevalence of relevant K13-propeller gene polymorphisms in parasite isolates from the north-western region of Benin.. Plasmodium falciparum isolates were collected from children with a confirmed diagnosis of malaria aged 6 months to 5 years in two towns, Cobly and Djougou, in the north-western part of Benin. The study was conducted during the rainy season from July to November 2014 in local health facilities. The K13-propeller gene was amplified in parasite isolates using nested PCR and subsequently sequenced.. A total of 108 children were recruited into the study. The efficiency of amplification reactions was 72% (78/108). The propeller domain of the K13 gene was successfully sequenced in 78 P. falciparum isolates; all of them were wild type with no polymorphisms detectable.. The absence of mutations in the K13 gene indicates that P. falciparum parasite populations in the study area are still fully susceptible to artemisinins.

Topics: Anti-Infective Agents; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Benin; Child, Preschool; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Sequence Alignment

Countries remain reluctant to adopt the 2012 World Health Organization recommendation for single low-dose (0.25 mg/kg) primaquine (SLD PQ) for Plasmodium falciparum transmission-blocking due to concerns over drug-related haemolysis risk, especially among glucose-6-phosphate dehydrogenase-deficient (G6PDd) people, without evidence demonstrating that it can be safely deployed in their settings. Pharmacovigilance methods provide a systematic way of collecting safety data and supporting the rollout of SLD PQ.. The Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT), comprising: (1) a standardized form to support the surveillance of possible adverse events following SLD PQ treatment; (2) a patient information card to enhance awareness of known adverse drug reactions of SLD PQ use; and (3) a database compiling recorded information, was developed and piloted. Data on patient characteristics, malaria diagnosis and treatment are collected. Blood samples are taken to measure haemoglobin (Hb) and test for G6PD deficiency. Active follow-up includes a repeat Hb measurement and adverse event monitoring on or near day 7. A 13-month prospective pilot study in two hospital facilities in Swaziland alongside the introduction of SLD PQ generated preliminary evidence on the feasibility and acceptability of PROMPT.. PROMPT was well received by nurses as a simple, pragmatic approach to active surveillance of SLD PQ safety data. Of the 102 patients enrolled and administered SLD PQ, none were G6PDd. 93 (91.2 %) returned on or near day 7 for follow-up. Four (4.6 %) patients had falls in Hb ≥25 % from baseline, none of whom presented with signs or symptoms of anaemia. No patient's Hb fell below 7 g/dL and none required a blood transfusion. Of the 11 (11 %) patients who reported an adverse event over the study period, three were considered serious and included two deaths and one hospitalization; none were causally related to SLD PQ. Four non-serious adverse events were considered definitely, probably, or possibly related to SLD PQ.. Improved pharmacovigilance to monitor and promote the safety of the WHO recommendation is needed. The successful application of PROMPT demonstrates its potential as an important tool to rapidly generate locally acquired safety data and support pharmacovigilance in resource-limited settings.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Eswatini; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Pharmacovigilance; Pilot Projects; Primaquine; Product Surveillance, Postmarketing; Prospective Studies; Young Adult

The use of artemisinin as a monotherapy resulted in the emergence of artemisinin resistance in 2005 in Southeast Asia. Monitoring of artemisinin combination therapy (ACT) is critical in order to detect and prevent the spread of resistance in endemic areas. Ex vivo studies and genotyping of molecular markers of resistance can be used as part of this routine monitoring strategy. One gene that has been associated in some ACT partner drug resistance is the Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene. The purpose of this study was to assess the drug susceptibility of P. falciparum populations from Thiès, Senegal by ex vivo assay and typing molecular markers of resistance to drug components of ACT currently used for treatment.. The ex vivo susceptibility of 170 P. falciparum isolates to chloroquine, amodiaquine, lumefantrine, artesunate, and artemether was determined using the DAPI ex vivo assay. The high resolution melting technique was used to genotype the pfmdr1 gene at codons 86, 184 and 1246.. A significant decrease in IC50 values was observed between 2012 and 2013: from 13.84 to 6.484 for amodiaquine, 173.4 to 113.2 for lumefantrine, and 39.72 to 18.29 for chloroquine, respectively. Increase of the wild haplotype NYD and the decrease of the mutant haplotype NFD (79 and 62.26 %) was also observed. A correlation was observed between the wild type allele Y184 in pfmdr1 and higher IC50 for all drugs, except amodiaquine.. This study has shown an increase in sensitivity over the span of two transmission seasons, marked by an increase in the WT alleles at pfmdr1. Continuous the monitoring of the ACT used for treatment of uncomplicated malaria will be helpful.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Gene Frequency; Genetics, Population; Genotyping Techniques; Haplotypes; Humans; Malaria, Falciparum; Male; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Selection, Genetic; Senegal; Young Adult

Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required.. This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680.. A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples.. AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Fluorenes; Humans; India; Infant; Malaria, Falciparum; Merozoite Surface Protein 1; Middle Aged; Plasmodium falciparum; Prospective Studies; Protozoan Proteins; Sequence Analysis, DNA; Treatment Outcome; Young Adult

Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without.. Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF - Plumpy'Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7.. A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8-100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4-99.7 %) at day 28 and 98.3 % (95.6-99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04-4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049).. This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7.. ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Mali; Niger; Severe Acute Malnutrition

The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated Plasmodium falciparum monoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.

Topics: Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Quinolines; Treatment Failure

Atovaquone-proguanil (AP) and artemether-lumefantrine (AL) are both treatments for uncomplicated Plasmodium falciparum malaria, but comparative clinical trials are lacking. We performed a retrospective analysis, comparing treatment failure and fever clearance time in non-immune travelers with uncomplicated P. falciparum malaria, treated with AP or AL. Sixty-nine patients were included during 2001-2013: 44 in the AP group and 25 in the AL group. Treatment failure was observed in 6 of 44 (13.6%) and 1 of 25 (4.0%) patients in the AP and AL groups, respectively. Six treatment failures were observed in travelers from West Africa. Fever clearance time was 44 ± 23 h in AL group versus 77 ± 28 h in AP group, (P < 0.001). Hospitalization time was significantly shorter in the AL group; 3.8 + 1.3 versus 5.1 + 2.8 days in the AP group (P = 0.04) In conclusion, travelers with uncomplicated P. falciparum malaria recover faster on AL than on AP. The AL should probably be the drug of choice for this population.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Atovaquone; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Proguanil; Travel

Plasmodium falciparum Pfcrt-76 and Pfmdr1-86 gene polymorphisms were determined during a clinical trial in Burkina Faso comparing the efficacies of dihydroartemisinin-piperaquine (DHA-PPQ) and artemether-lumefantrine (AL). Significant selection of Pfcrt-K76 was observed after exposure to AL and DHA-PPQ, as well as selection of Pfmdr1-N86 after AL but not DHA-PPQ treatment, suggesting reverse selection on the Pfcrt gene by PPQ. These results support the rational use of DHA-PPQ in settings where chloroquine (CQ) resistance is high.

Topics: Antimanic Agents; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Genetic Variation; Humans; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Protozoan Proteins; Quinolines

The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04). The high frequency of Pfmspdbl2 codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem).

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Codon; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Kenya; Lumefantrine; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins

Antimalarial drugs are a powerful tool for malaria control and elimination. Artemisinin-based combination therapies (ACTs) can reduce transmission when widely distributed in a campaign setting. Modelling mass antimalarial campaigns can elucidate how to most effectively deploy drug-based interventions and quantitatively compare the effects of cure, prophylaxis, and transmission-blocking in suppressing parasite prevalence.. A previously established agent-based model that includes innate and adaptive immunity was used to simulate malaria infections and transmission. Pharmacokinetics of artemether, lumefantrine, dihydroartemisinin, piperaquine, and primaquine were modelled with a double-exponential distribution-elimination model including weight-dependent parameters and age-dependent dosing. Drug killing of asexual parasites and gametocytes was calibrated to clinical data. Mass distribution of ACTs and primaquine was simulated with seasonal mosquito dynamics at a range of transmission intensities.. A single mass campaign with antimalarial drugs is insufficient to permanently reduce malaria prevalence when transmission is high. Current diagnostics are insufficiently sensitive to accurately identify asymptomatic infections, and mass-screen-and-treat campaigns are much less efficacious than mass drug administrations. Improving campaign coverage leads to decreased prevalence one month after the end of the campaign, while increasing compliance lengthens the duration of protection against reinfection. Use of a long-lasting prophylactic as part of a mass drug administration regimen confers the most benefit under conditions of high transmission and moderately high coverage. Addition of primaquine can reduce prevalence but exerts its largest effect when coupled with a long-lasting prophylactic.. Mass administration of antimalarial drugs can be a powerful tool to reduce prevalence for a few months post-campaign. A slow-decaying prophylactic administered with a parasite-clearing drug offers strong protection against reinfection, especially in highly endemic areas. Transmission-blocking drugs have only limited effects unless administered with a prophylactic under very high coverage.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Models, Biological; Post-Exposure Prophylaxis; Prevalence; Primaquine; Quinolines; Young Adult; Zambia

The resistance of malaria parasites to sulphadoxine-pyrimethamine (SP) in 2007 led to the Malawi Ministry of Health changing to artemether-lumefantrine (AL) as first-line for uncomplicated malaria treatment. This study determined the efficacy and safety of AL for the treatment of uncomplicated Plasmodium falciparum malaria among six to 59 months old Malawian children.. This was a prospective study of children six to 59 months old treated with AL after presenting with uncomplicated malaria in the six health facilities in Malawi. The children were followed up on days 1, 2, 3, 7, 14, 21 and 28 days post-treatment and assessed for clinical and parasitological responses. The Kaplan Meier survival estimate was used to measure the efficacy of AL by calculating the cumulative risk of failure at day 28.. A total of 322 children were recruited into the study across the six sites. The overall intention-to-treat (ITT) polymerase chain reaction (PCR)-corrected cure rate was 93.4%. Per protocol overall PCR-corrected cure rates for the study sites were; Karonga 98.0%, Kawale 97.4%, Machinga 90.2%, Mangochi 95.4% and Rumphi 91.3%. Nkhotakota study site had the lowest cure rate of 78.0%.. There is evidence of good efficacy of AL in Malawi notwithstanding geographical contrasts and this supports the continued use of AL as the first-line treatment for uncomplicated malaria. However there may be need to further investigate the comparatively low efficacy rate found in Nkhotakota district in order to identify possible determinants of treatment failure.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Kaplan-Meier Estimate; Malaria, Falciparum; Malawi; Male; Prospective Studies; Treatment Failure

Drug resistance is one of the main reasons of anti-malarial treatment failures and impedes malaria containment strategies. As single nucleotide polymorphisms (SNPs) have been found to correlate with anti-malarial drug resistance, the surveillance strategy includes continuous monitoring of known molecular markers and detection of new mutation patterns. With the introduction of artemisinin-based combination therapy, selection of specific patterns has been observed worldwide.. From March to June 2013, whole blood was collected on filter paper from microscopically malaria positive patients in Jimma zone (District), southwestern Ethiopia. Plasmodium falciparum, Plasmodium vivax and mixed infections were included. SNPs were investigated by conventional or real-time PCR, restriction fragment length pattern analysis or sequencing. Results were compared to molecular patterns from Ethiopian isolates in 2004, 2006 and 2008/9.. Plasmodium falciparum, P. vivax, and mixed infections were molecularly confirmed in 177, 80, and 14 samples, respectively. In P. falciparum, mutations in the pfcrt, pfmdr 1and pfATP 6 (SERCA) gene were investigated. Whereas the mutation in the pfcrt gene at codon 76 K was still found in 95.6% of all samples, the pfmdr 1 86 T mutation fell to 1.2% (2/163) in 2013 compared to 9% in 2008/9 and 86% in 2006 (P<0.001). The pfmdr 1 184 F mutation dominated with 100.0% (172/172) in 2013. Sequencing of the recently reported PF3D7_1343700 kelch propeller domain showed no mutation at codon 476. First sequencing data of the pvmdr 1 gene from Jimma region revealed a prevalence of the mutations 976 F and 1076 L in 72.7% (16/23) and 100.0% (19/19) of the isolates, respectively.. Since the introduction of artemether-lumefantrine (AL) in Jimma, Ethiopia, in 2006, the prevalence of certain SNPs associated with AL use has increased. Markers for chloroquine resistance in P. vivax were highly frequent. Continuous molecular and clinical surveillance are of paramount importance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Plasmodium falciparum; Plasmodium vivax; Prevalence; Protozoan Proteins; Real-Time Polymerase Chain Reaction; Seasons; Young Adult

Malaria is a complex disease, which varies in its epidemiology and clinical manifestation. Although artemether-lumefantrine has been used as first-line drug for uncomplicated Plasmodium falciparum malaria in Bahir Dar district since 2004, its efficacy has not yet been assessed. The main objective of this study was to quantify the proportion of patients with uncomplicated falciparum malaria who were prescribed artemether-lumefantrine and who failed treatment after a 28-day follow-up.. The research team attempted to conduct an observational cohort study on the assessment of therapeutic efficacy and safety of artemether-lumefantrine in falciparum malaria patients aged over five years in Bahir Dar district from March to July 2012.. Among 130 participants in the study, 60% were males with 1:5 male to female ratio. The mean of asexual parasitaemia load was 8675 parasites/μL and 96.1% participants were free from parasitaemia at day 3. At the end of the study, 98.5% of participants showed adequate clinical and parasitological response of the drug. In the study, only 1.5% of participants were shown late parasitological failure between seventh and 14th day follow-up and 1.3% of participants were free from anaemia at the end of follow-up.. According to the research findings, artemether-lumefantrine fulfilled the inclusion criteria of WHO as first-line drug and continues to be the drug of choice for the treatment of uncomplicated falciparum malaria. Outputs from this study should be supported through advanced molecular techniques and blood concentration and pharmaco-vigilance of the drug.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cohort Studies; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Treatment Outcome; Young Adult

Plasmodium falciparum accounts for approximately 60% of malaria cases in Ethiopia and artemether-lumefantrine has been used as a first-line treatment for uncomplicated P. falciparum malaria since 2004. The aim of this study was to assess the therapeutic efficacy of artemether-lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in north-western Ethiopia.. A 28-day one-arm, prospective evaluation of the clinical and parasitological response to the first-line treatment for uncomplicated P. falciparum malaria was conducted in Enfranze Health Centre in accordance with the 2009 WHO efficacy study guidelines. Patients were treated with a 3-day course of AL and clinical and parasitological parameters were monitored over a 28-day follow-up. All data from recruited patients were imported into an electronic data base and Kaplan-Meier survival analysis was used for analysing primary [early treatment failures (ETF), late clinical failure (LCF), late parasitological failures (LPF), and adequate clinical and parasitological response (ACPR)] and secondary (PCT, GCT and FCT) outcomes.. Eighty patients were enrolled and all of them completed the 28-day follow-up period. The PCR-corrected cure rate was 95.0% (95% CI 87.0-98.4%) and there were two ETF, one LCF and three LPF. Two of the LPF were classified as re infections by PCR. Seventy three point seven five percent, 91.25 and 95% of patients had cleared their parasitaemia by days 1, 2, and 3, respectively, and 75, 91.25 and 96.25% of patients had cleared their fever by days 1, 2, and 3. All patients completely cleared their gametocytes by day 7.. The relatively high cure rate, low proportion of patients still positive on day 3 as well as parasite clearance times in this study would indicate no imminent threat of artemisinin resistance development in the region. However, the threat of spreading or de novo development of artemisinin resistance warrants regular monitoring of drug efficacy throughout the region.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Prospective Studies; Young Adult

The long half-lives of malaria 'partner' drugs are a potent force selecting for drug resistance. Clinical trials can quantify this effect by estimating a window of selection (WoS), defined as the amount of time post-treatment when drug levels are sufficiently high that resistant parasites can re-establish an infection while preventing drug-sensitive parasites from establishing viable infections.. The ability of clinical data to accurately estimate the true WoS was investigated using standard pharmacokinetic-pharmacodynamic models for three widely used malaria drugs: artemether-lumefantrine (AR-LF), artesunate-mefloquine (AS-MQ) and dihydroartemisinin-piperaquine (DHA-PPQ). Estimates of the clinical WoS either (1) ignored all new infections occurring after the 63-day follow-up period, as is currently done in clinical trials, or, (2) recognized that all individuals would eventually be re-infected and arbitrarily assigned them a new infection day.. The results suggest current methods of estimating the clinical WoS underestimate the true WoS by as much as 9 days for AR-LF, 33 days for AS-MQ and 7 days for DHA-PPQ. The new method of estimating clinical WoS (i.e., retaining all individuals in the analysis) was significantly better at estimating the true WoS for AR-LF and AS-MQ.. Previous studies, based on clinically observed WoS, have probably underestimated the 'true' WoS and hence the role of drugs with long half-lives in driving resistance. This has important policy implications: high levels of drug use are inevitable in mass drug administration programmes and intermittent preventative treatment programmes and the analysis herein suggests these policies will be far more potent drivers of resistance than previously thought.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Models, Biological; Plasmodium falciparum; Quinolines

Artemether-lumefantrine (AL) became the first-line treatment for uncomplicated malaria in Kenya in 2006. Studies have shown AL selects for SNPs in pfcrt and pfmdr1 genes in recurring parasites compared to the baseline infections. The genotypes associated with AL selection are K76 in pfcrt and N86, 184F and D1246 in pfmdr1. To assess the temporal change of these genotypes in western Kenya, 47 parasite isolates collected before (pre-ACT; 1995-2003) and 745 after (post-ACT; 2008-2014) introduction of AL were analyzed. In addition, the associations of parasite haplotype against the IC50 of artemether and lumefantrine, and clearance rates were determined. Parasite genomic DNA collected between 1995 and 2014 was analyzed by sequencing or PCR-based single-base extension on Sequenom MassARRAY. IC50s were determined for a subset of the samples. One hundred eighteen samples from 2013 to 2014 were from an efficacy trial of which 68 had clearance half-lives. Data revealed there were significant differences between pre-ACT and post-ACT genotypes at the four codons (chi-square analysis; p < 0.0001). The prevalence of pfcrt K76 and N86 increased from 6.4% in 1995-1996 to 93.2% in 2014 and 0.0% in 2002-2003 to 92.4% in 2014 respectively. Analysis of parasites carrying pure alleles of K + NFD or T + YYY haplotypes revealed that 100.0% of the pre-ACT parasites carried T + YYY and 99.3% of post-ACT parasites carried K + NFD. There was significant correlation (p = 0.04) between lumefantrine IC50 and polymorphism at pfmdr1 codon 184. There was no difference in parasite clearance half-lives based on genetic haplotype profiles. This study shows there is a significant change in parasite genotype, with key molecular determinants of AL selection almost reaching saturation. The implications of these findings are not clear since AL remains highly efficacious. However, there is need to closely monitor parasite genotypic, phenotypic and clinical dynamics in response to continued use of AL in western Kenya.

Topics: Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Drug Combinations; Ethanolamines; Fluorenes; Gene Expression Regulation; Haplotypes; Humans; Kenya; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Protozoan Proteins; Selection, Genetic; Time Factors

There is considerable concern that malaria parasites are starting to evolve resistance to the current generation of antimalarial drugs, the artemisinin-based combination therapies (ACTs). We use pharmacological modeling to investigate changes in ACT effectiveness likely to occur if current regimens are extended from 3 to 5 days or, alternatively, given twice daily over 3 days. We show that the pharmacology of artemisinins allows both regimen changes to substantially increase the artemisinin killing rate. Malaria patients rarely contain more than 10(12) parasites, while the standard dosing regimens allow approximately 1 in 10(10) parasites to survive artemisinin treatment. Parasite survival falls dramatically, to around 1 in 10(17) parasites if the dose is extended or split; theoretically, this increase in drug killing appears to be more than sufficient to restore failing ACT efficacy. One of the most widely used dosing regimens, artemether-lumefantrine, already successfully employs a twice-daily dosing regimen, and we argue that twice-daily dosing should be incorporated into all ACT regimen design considerations as a simple and effective way of ensuring the continued long-term effectiveness of ACTs.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Dosage Calculations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Models, Statistical; Parasitic Sensitivity Tests; Plasmodium falciparum; Pregnancy; Treatment Outcome

Malaria disproportionately affects young children. Clinical trials in African children showed that dihydroartemisinin-piperaquine (DP) is an effective antimalarial and has a longer posttreatment prophylactic (PTP) effect against reinfections than other artemisinin-based combination therapies, including artemether-lumefantrine (AL). Using a previously developed Markov model and individual patient data from a multicenter African drug efficacy trial, we assessed the economic value of the PTP effect of DP versus AL in pediatric malaria patients from health-care provider's perspective in low-to-moderate and moderate-to-high transmission settings under different drug co-payment scenarios. In low-to-moderate transmission settings, first-line treatment with DP was highly cost-effective with an incremental cost-effectiveness ratio of US$5 (95% confidence interval [CI] = -76 to 196) per disability-adjusted life year (DALY) averted. In moderate-to-high transmission settings, DP first-line treatment led to a mean cost saving of US$1.09 (95% CI = -0.88 to 3.85) and averted 0.05 (95% CI = -0.08 to 0.22) DALYs per child per year. Our results suggested that DP might be superior to AL for first-line treatment of uncomplicated childhood malaria across a range of transmission settings in Africa.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Markov Chains; Models, Biological; Models, Economic; Plasmodium falciparum; Quinolines; Recurrence

Data from clinical studies show that artemether-lumefantrine (AL) is effective and well tolerated in adults and children with uncomplicated Plasmodium falciparum malaria. However, data on effectiveness and safety of AL in patients in non-endemic settings are limited.. A 5-year surveillance plan included all AL-treated adult and paediatric patients with confirmed or suspected P. falciparum malaria in the USA, as reported to the National Malaria Surveillance System at the Centers for Disease Control and Prevention. Descriptive analyses included demographics, baseline characteristics, clinical effectiveness, and safety. From May 2010 to April 2015, demographics and baseline characteristics were collected for 203 patients and safety data for 108 patients. Treatment effectiveness data at day 7 were collected for 117 patients and at day 28 for 98 patients.. The majority of patients were male (58.6 %), Black (62.6 %), non-Hispanic (92.6 %), and likely malaria non-immune (80.8 %). The median age was 32 (range 1-88) years and the median body mass index was 25.5 (range 13.8-42.4) kg/m(2). All patients with effectiveness data had confirmed (n = 116) or suspected (n = 1) malaria. The overall cure rate for patients treated with AL was 91.5 % (95 % CI 84.8-95.8 %) at day 7 and 96.9 % (95 % CI 91.3-99.4 %) at day 28. Adverse events were reported in four (3.7 %) patients, and there were no new or unexpected safety signals.. AL was effective and well tolerated in the treatment of likely non-immune patients with P. falciparum malaria.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Retrospective Studies; United States; Young Adult

Plasmodium falciparum isolates were collected from 29 malaria patients treated with artemether-lumefantrine in Mayotte in 2013 and 2014. Twenty-four cases (83%) consisted of imported malaria. Seventeen percent of the isolates presented mutations in one of the six K13-propeller blades (N490H, F495L, N554H/K, and E596G). A total of 23.8% of the isolates from the Union of Comoros showed K13-propeller polymorphisms. Three of the 18 isolates (16.7%) from Grande Comore showed polymorphisms (N490H, N554K, and E596G).

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Comoros; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Mutation; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Retrospective Studies

Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs.. With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution.. Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread.. Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients.. Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Administration Schedule; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Models, Biological; Plasmodium falciparum; Quinolines; Treatment Failure

Drug resistance in Plasmodium falciparum has posed an obstacle to effective treatment and challenges many malaria control programmes in endemic areas. In Angola, until 2003, chloroquine (CQ) was used as first-line therapy for uncomplicated malaria. It was replaced initially by amodiaquine and, in 2006, by artemisinin-based combination therapy (ACT) with artemether-lumefantrine (AL, Coartem(®)). Efficacy study of ACT, conducted in Angola between 2004 and 2005, showed a baseline efficacy of ≈99%.. 103 malaria patients were enrolled according to WHO proceedings. Patients were followed up with clinical and parasitological evaluations for 28 days, parasite density and identification was evaluated by microscopy, the pfmsp2 were genotyped by nested-PCR, to distinguish parasite recrudescence from new infections; the polymorphisms at codons 86 and 1246 of pfmdr1 gene, and 769 of pfatp6 gene were assessed by PCR-RFLP and sequencing for pfk13-propeller genotype.. The cure rate was 91.3%. The obtained results showed that from 103 patients, 12.6% (n = 13) still had parasitaemia 1 day after the treatment was finished. On day 0, of the 94 evaluated samples, wild-type alleles were identified in 73.4% (n = 69) for pfmdr1 N86Y position and only one sample carried the mutant allele (Y) for pfmdr1 1246; 14% of these samples showed increased pfmdr1 copy number; 100% (n = 21) had wild-type allele of k13 gene in all the studied positions.. These results showed changes in parasite profile susceptibility to AL in comparison to the baseline data from 2002 to 2004 and on the genotyping characteristics; the clinical outcome after treatment with AL did not link a particular genotype with treatment failure; observed changes do not provide sufficient evidence for a treatment policy change, but they suggest that a carefully monitoring is needed in this area.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Calcium-Transporting ATPases; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genotyping Techniques; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prospective Studies; Treatment Outcome; Young Adult

Malaria and salmonella infections are endemic especially in developing countries, however malaria and salmonella co-infection is a rare entity with high mortality. The basic mechanism in developing salmonella co-infection is the impaired mobilization of granulocytes through heme and heme oxygenase which are released from haemoglobin due to the breakdown of erythrocytes during malaria infection. Thus, a malaria infected person becomes more susceptible to develop infection with Salmonella spp. In this report a case with Plasmodium falciparum and Salmonella Typhi co-infection was presented. A 23-year-old male patient was admitted to hospital with the complaints of diarrhea, nausea, vomiting, abdominal pain, fatigue and fever. Laboratory findings yielded decreased number of platelets and increased ALT, AST and CRP levels. Since he had a history of working in Pakistan, malaria infection was considered in differential diagnosis, and the diagnosis was confirmed by the detection of P.falciparum trophozoites in the thick and thin blood smears. As he came from a region with chloroquine-resistant Plasmodium, quinine (3 x 650 mg) and doxycycline (2 x 100 mg/day) were started for the treatment. No erythrocytes, parasite eggs or fungal elements were seen at the stool microscopy of the patient who had diarrhoea during admission. No pathogenic microorganism growth was detected in his stool culture. The patient's blood cultures were also taken in febrile periods starting from the time of his hospitalization. A bacterial growth was observed in his blood cultures, and the isolate was identified as S. Typhi. Thus, the patient was diagnosed with P.falciparum and Salmonella Typhi coinfection. Ceftriaxone (1 x 2 g/day, 14 days) was added to the therapy according to the results of antibiotic susceptibility test. With the combined therapy (quinine, doxycycline, ceftriaxone) the fever was taken under control, his general condition improved and laboratory findings turned to normal values. However, on the fifth day of his anti-malaria therapy sudden bilateral hearing loss developed due to quinine use. Thus, the treatment was replaced with an artemisinin-based (arthemeter/lumefantrine) combination therapy. No adverse effects were detected due to artemisinin-based therapy, and the patient completely recovered. In conclusion, if a patient is diagnosed with malaria, he/she should be closely monitored in terms of having co-infections and appropriate diagnostic methods including blood cul

Topics: Anti-Bacterial Agents; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bacteremia; Ceftriaxone; Coinfection; Diagnosis, Differential; Doxycycline; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Hearing Loss, Bilateral; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Quinine; Salmonella typhi; Treatment Outcome; Typhoid Fever; Young Adult

Malaria is a parasitic infection characterized by anemia, splenomegaly and periodic fever. This infection has a tendency to cause serious complications. Falciparum malaria could occur in our country as an imported case due to increasing intercontinental travel opportunities. The World Health Organisation (WHO) recommends arthemether combination treatment as a first line choice. Here we report a Turkish case admitted to the hospital with high fever, sweating and fatigue. He had been in Uganda for 6 months without prophylaxis. Plasmodium falciparum with an intense parasitic load was diagnosed. We started arthemether-lumefantrine combination therapy immediately. 18 days after his discharge he was readmitted with the same complaints and parasitemia was detected once again. This time, we treated him with the quinine-tetracycline combination regime for 7 days. Within 48 hours the patient was afebrile and the blood smear was negative. Falciparum malaria must be considered in infection emergencies for febrile patients especially with any travel history. For an initial therapy, arthemetherlumefantrine combination is a successful choice of treatment. Even with adequate treatment of arthemether-lumefantrine combination, the problems of recurrence (recrudescence or reinfection) could occur due to treatment failure. For the possibility of recurrence, close monitoring of patients is very important in the critical course after adequate treatment.

Topics: Administration, Oral; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fever; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Quinine; Recurrence; Tetracycline; Travel; Treatment Failure; Turkey; Uganda

Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistance-mediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003-2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008-2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Chloroquine; Clinical Trials as Topic; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genetic Markers; Humans; Infant; Malaria, Falciparum; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Mutation; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Time Factors; Uganda

Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter- and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] = 4.04; P value of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P = 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biological Availability; Biotransformation; Case-Control Studies; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Models, Statistical; Plasmodium falciparum; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Severity of Illness Index; Treatment Failure

Resistance to anti-malarials is a major public health problem worldwide. After deployment of artemisinin-based combination therapy (ACT) there have been reports of reduced sensitivity to ACT by malaria parasites in South-East Asia. In Tanzania, artemether-lumefantrine (ALu) is the recommended first-line drug in treatment of uncomplicated malaria. This study surveyed the distribution of the Plasmodium falciparum multidrug resistance protein-1 single nucleotide polymorphisms (SNPs) associated with increased parasite tolerance to ALu, in Tanzania.. A total of 687 Plasmodium falciparum positive dried blood spots on filter paper and rapid diagnostic test strips collected by finger pricks from patients attending health facilities in six regions of Tanzania mainland between June 2010 and August 2011 were used. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect Pfmdr1 SNPs N86Y, Y184F and D1246Y.. There were variations in the distribution of Pfmdr1 polymorphisms among regions. Tanga region had exceptionally high prevalence of mutant alleles, while Mbeya had the highest prevalence of wild type alleles. The haplotype YFY was exclusively most prevalent in Tanga (29.6%) whereas the NYD haplotype was the most prevalent in all other regions. Excluding Tanga and Mbeya, four, most common Pfmdr1 haplotypes did not vary between the remaining four regions (χ² = 2.3, p = 0.512). The NFD haplotype was the second most prevalent haplotype in all regions, ranging from 17% - 26%.. This is the first country-wide survey on Pfmdr1 mutations associated with ACT resistance. Distribution of individual Pfmdr1 mutations at codons 86, 184 and 1246 varies throughout Tanzanian regions. There is a general homogeneity in distribution of common Pfmdr1 haplotypes reflecting strict implementation of ALu policy in Tanzania with overall prevalence of NFD haplotype ranging from 17 to 26% among other haplotypes. With continuation of ALu as first-line drug this haplotype is expected to keep rising, thus there is need for continued pharmacovigilance studies to monitor any delayed parasite clearance by the drug.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Child, Preschool; Drug Combinations; Drug Resistance; Epidemiological Monitoring; Ethanolamines; Female; Fluorenes; Gene Frequency; Genotype; Haplotypes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Middle Aged; Mutation, Missense; Plasmodium falciparum; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Tanzania; Young Adult

Mozambique implemented artemisinin-based combinations therapy (ACT) using artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in 2009. AL remains highly efficacious, but widespread use may soon facilitate emergence of artemisinin tolerance/resistance. The prevalence of pfmdr1 different alleles in Maputo and Mozambique is not known, either after or before the introduction of ACT. Pfmdr1 molecular markers related to Plasmodium falciparum susceptibility were analysed before and after transition to ACT.. A first group of samples was collected between June 2003 and June 2005 and a second group in the period between March 2010 and March 2012. Three alleles were analysed by PCR-RFLP: N86Y, Y184F and D1246Y, in the pfmdr1 gene.. Alleles N86, 184F and D1246 increased from 19.5, 19.6 and 74.4% in 2003-2005 to 73.2, 22.7 and 96.7% in 2010-2012, respectively. After implementation of ACT (2010-2012), pfmdr1 haplotypes, either two- and three-codon basis, were generally less diverse than before the implementation of ACT (2003-2005). The prevalence of haplotypes N86-184Y, N86-D1246 and 184Y-D1246 increased from 12,2, 27.3 and 71.7% in 2003-2005 to 59.4, 84.3 and 78.6% in 2010-2012. The three-codon basis haplotypes NFD and NYD also increased significantly during the same period.. The alleles N86 and 184 F and the triple haplotype N86-184 F-D1246 showed a significantly increased prevalence after introduction of ACT.

Topics: Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Haplotypes; Humans; Malaria, Falciparum; Mozambique; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Prevalence

This study analysed the dynamics of blood stage malaria with immune response and under administration of Coartem as a combination therapy. The techniques of mathematical modelling were used in coming up and analysing the deterministic model. Sensitivity analysis and statistical approaches were used to compare model simulated treatment results with the use of Coartem and other antimalarial drugs. We sought to theoretically assess if Coartem can bring improvement in the treatment of malaria as compared to the other drugs. Our analysis and numerical results suggest that Coartem compares well with other antimalarial drug that have been on the market. However, the shortfall of our model is that it could not give good comparative results between Coartem treatment and other combination treatment schemes with similar mode of action. Our study predicted effects of different drug treatment protocols in malaria using a theoretical mathematical model, which gives an insight into potential effective treatment schemes.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Models, Theoretical; Treatment Outcome

Anti-malarial drug resistance continues to be a leading threat to ongoing malaria control efforts and calls for continued monitoring of the efficacy of these drugs in order to inform national anti-malarial drug policy decision-making. This study assessed the therapeutic efficacy and safety of artemether-lumefantrine (AL)(Coartem®) for the treatment of uncomplicated Plasmodium falciparum malaria in two sentinel high malaria transmission districts in the Eastern Province of Zambia in persons aged six months and above, excluding women aged 12 to 18 years.. This was an observational cohort of 176 symptomatic patients diagnosed with uncomplicated Plasmodium falciparum mono-infection. A World Health Organization (WHO)-standardized 28-day assessment protocol was used to assess clinical and parasitological responses to directly observed AL treatment of uncomplicated malaria. DNA polymerase chain reaction (PCR) analysis for molecular markers of AL resistance was conducted on positive blood samples and differentiated recrudescence from re-infections of the malaria parasites.. All patients (CI 97.6-100) had adequate clinical and parasitological responses to treatment with AL. At the time of enrolment, mean slide positivity among study participants was 71.8% and 55.2% in Katete and Chipata, respectively. From a mean parasite density of 55,087, 98% of the study participants presented with zero parasitaemia by day 3 of the study. Fever clearance occurred within 24 hours of treatment with AL. However mean parasite density declines were most dramatic in participants in the older age. No adverse reactions to AL treatment were observed during the study.. AL remains a safe and efficacious drug for the treatment of uncomplicated Plasmodium falciparum malaria in Zambia, endemic for malaria, with some provinces experiencing high transmission intensity. However, the delayed parasite clearance in younger patients calls for further sentinel and periodical monitoring of AL efficacy in different areas of the country.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cohort Studies; DNA, Protozoan; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Prospective Studies; Treatment Outcome; Young Adult; Zambia

Topics: Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Quinolines

Development and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) constitutes a major threat to recent global malaria control achievements. Surveillance of molecular markers could act as an early warning system of ACT-resistance before clinical treatment failures are apparent. The aim of this study was to analyse temporal trends of established genotypes associated with artemether-lumefantrine tolerance/resistance before and after its deployment as first-line treatment for uncomplicated malaria in Tanzania 2006.. Single nucleotide polymorphisms in the P. falciparum multidrug resistance gene 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine transporter gene (pfcrt) K76T were analysed from dried blood spots collected during six consecutive studies from children with uncomplicated P. falciparum malaria in Fukayosi village, Bagamoyo District, Tanzania, between 2004-2011.. There was a statistically significant yearly increase of pfmdr1 N86, 184F, D1246 and pfcrt K76 between 2006-2011 from 14% to 61% (yearly OR = 1.38 [95% CI 1.25-1.52] p < 0.0001), 14% to 35% (OR = 1.17 [95% CI 1.07-1.30] p = 0.001), 54% to 85% (OR = 1.21 [95% CI 1.03-1.42] p = 0.016) and 49% to 85% (OR = 1.33 [95% CI 1.17-1.51] p < 0.0001), respectively. Unlike for the pfmdr1 SNP, a significant increase of pfcrt K76 was observed already between 2004-2006, from 26% to 49% (OR = 1.68 [95% CI 1.17-2.40] p = 0.005). From 2006 to 2011 the pfmdr1 NFD haplotype increased from 10% to 37% (OR = 1.25 [95% CI 1.12-1.39] p < 0.0001), whereas the YYY haplotype decreased from 31% to 6% (OR = 0.73 [95% CI 0.56-0.98] p = 0.018). All 390 successfully analysed samples had one copy of the pfmdr1 gene.. The temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy in Tanzania and emphasizes the importance of molecular surveillance as a complement to standard in vivo trials.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Genetic Markers; Genotype; Humans; Infant; Malaria, Falciparum; Male; Mutation, Missense; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Tanzania; Time Factors

Artemisinin and its derivatives are essential components of artemisinin-based combination therapies for treating severe falciparum malaria. In this paper, we describe the occurrence of haemolysis after oral artemether-lumefantrine treatment. To the best of our knowledge, this is the second reported case of a patient affected by severe falciparum malaria with haemolytic anaemia that is likely associated with oral artemether-lumefantrine treatment.

Topics: Administration, Oral; Anemia, Hemolytic; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged

Malaria rapid diagnostic tests (RDT) are used for diagnostic purpose in malaria-endemic areas where reliable microscopy is not available. Persistence of the antigenaemia causes over-diagnosis and may limit the usefulness of the RDT in monitoring treatment. In this study, the usefulness of histidine-rich protein-2 (HRP2) and pan-specific or species-specific Plasmodium lactate dehydrogenase (pLDH) in treatment monitoring of uncomplicated falciparum malaria was carried out in an endemic setting in Myanmar.. A prospective longitudinal, single-arm, cohort study was done by microscopy to confirm Plasmodium falciparum mono-infected cases. After direct treatment with an artemether-lumefantrine combination, patients were followed up on day 3, 7, 14, 21, 28 and any other day of recurrent fever. Blood film examination and RDT were carried out on day 0 and all follow-up days.. Out of 77 recruited falciparum cases, 63 became adequate clinical and parasitological response (ACPR) cases, and 60.3% of them were still positive for HRP2 up to day 28. Eleven out of 12 treatment failure cases (91.6%) were detected by pan pLDH. The mean duration required to become negative of HRP2 was 20 days (SD ± 6.03) and that of pan pLDH was six days with or without gametocytes and 3.7 days without gametocytes.. Although treatment monitoring cannot be performed by HRP2, it can be assessed by pan pLDH-based assay after day 3 if a gametocidal drug has been administered and after day 7 if the presence of gametocytes was not excluded. The pan pLDH-based assay was a suitable test to monitor the treatment response of uncomplicated falciparum malaria patients.

Topics: Adolescent; Adult; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Chromatography, Affinity; Drug Combinations; Drug Monitoring; Ethanolamines; Female; Fluorenes; Humans; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Middle Aged; Myanmar; Parasite Load; Plasmodium falciparum; Prospective Studies; Protozoan Proteins; Reagent Kits, Diagnostic; Sensitivity and Specificity; Young Adult

The authors present a case of severe falciparum malaria diagnosed in a traveler after he returned to Rhode Island from a visit to the Dominican Republic. They then review aspects of the case pertinent to our local practice environment that make diagnosis and management especially challenging.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Diagnosis, Differential; Dominican Republic; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Practice Guidelines as Topic; Quinidine; Rhode Island; Travel; Treatment Outcome

In 2007 Timor-Leste, a malaria endemic country, changed its Malaria Treatment Protocol for uncomplicated falciparum malaria from sulphadoxine-pyrimethamine to artemether-lumefantrine. The change in treatment policy was based on the rise in morbidity due to malaria and perception of increasing drug resistance. Despite a lack of nationally available evidence on drug resistance, the Ministry of Health decided to change the protocol. The policy process leading to this change was examined through a qualitative study on how the country developed its revised treatment protocol for malaria. This process involved many actors and was led by the Timor-Leste Ministry of Health and the WHO country office. This paper examines the challenges and opportunities identified during this period of treatment protocol change.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Clinical Protocols; Cooperative Behavior; Drug Combinations; Drug Substitution; Ethanolamines; Fluorenes; Health Planning Organizations; Health Policy; Humans; Interinstitutional Relations; Malaria, Falciparum; Policy Making; Pyrimethamine; Sulfadoxine; Time Factors; Timor-Leste

The distribution of both malaria and schistosomiasis exhibits a large geographical overlap in tropical environments, particularly in sub-Saharan Africa. This part of the world currently harbours more than 85% of the estimated global burden of these diseases. Studies showed that artemisinin derivatives used for the treatment of malaria also have an antischistosomal effect. This study aimed to investigate the extent of malaria-schistosomiasis co-infection and the antischistosomal effect of artemether-lumefantrine when administered to treat falciparum malaria in Kemise, Northeast Ethiopia.. Stool samples were collected from 152 microscopically confirmed malaria patients and diagnosed for schistosomiasis using the Kato-Katz technique before treatment. The schistosomiasis cure rate and egg reduction were determined in co-infected patients, who were treated with artemether-lumefantrine,.. Twenty-eight out of 152 malaria patients were co-infected (18.4%, n = 152) with schistosomiasis. All 28 co-infected patients were found stool-negative for Schistosoma mansoni eggs four weeks after treatment. The extent of co-infection was associated with age, sex and educational level. Cure rate and egg reduction rate following the treatment of artemether-lumefantrine were 100%.. The co-infection rate was associated with patient characteristics. Artemether-lumefantrine was effective against S. mansoni in co-infected patient. Multicenter and randomized trials, however, are needed for a better understanding of the efficacy of artemether-lumefantrine against schistosome infection with ranges of intensity.

Topics: Adolescent; Adult; Animals; Anthelmintics; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Coinfection; Drug Combinations; Ethanolamines; Ethiopia; Feces; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Parasite Egg Count; Plasmodium falciparum; Schistosoma mansoni; Schistosomiasis mansoni; Young Adult

Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic Plasmodium falciparum infections by microscopy. Post hoc PCR analysis confirmed the presence of P. falciparum in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (P = 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on in vivo malaria treatment outcomes in HIV-infected patients are thus needed.

Topics: Adult; Anti-HIV Agents; Antimalarials; Antiretroviral Therapy, Highly Active; Artemether, Lumefantrine Drug Combination; Artemisinins; Case-Control Studies; Coinfection; Drug Combinations; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Malaria, Falciparum; Male; Nevirapine; Nigeria

Rapid diagnostic test (RDT) is an important tool for parasite-based malaria diagnosis. High specificity of RDTs to distinguish an active Plasmodium falciparum infection from residual antigens from a previous infection is crucial in endemic areas where residents are repeatedly exposed to malaria. The efficiency of two RDTs based on histidine-rich protein 2 (HRP2) and lactate dehydrogenase (LDH) antigens were studied and compared with two microscopy techniques (Giemsa and acridine orange-stained blood smears) and real-time polymerase chain reaction (PCR) for assessment of initial clearance and detection of recurrent P. falciparum infections after artemisinin-based combination therapy (ACT) in a moderately high endemic area of rural Tanzania.. In this exploratory study 53 children < five years with uncomplicated P. falciparum malaria infection were followed up on nine occasions, i.e., day 1, 2, 3, 7, 14, 21, 28, 35 and 42, after initiation of artemether-lumefantrine treatment. At each visit capillary blood samples was collected for the HRP2 and LDH-based RDTs, Giemsa and acridine orange-stained blood smears for microscopy and real-time PCR. Assessment of clearance times and detection of recurrent P. falciparum infections were done for all diagnostic methods.. The median clearance times were 28 (range seven to >42) and seven (two to 14) days for HRP2 and LDH-based RDTs, two (one to seven) and two (one to 14) days for Giemsa and acridine orange-stained blood smear and two (one to 28) days for real-time PCR. RDT specificity against Giemsa-stained blood smear microscopy was 21% for HRP2 on day 14, reaching 87% on day 42, and ≥96% from day 14 to 42 for LDH. There was no significant correlation between parasite density at enrolment and duration of HRP2 positivity (r = 0.13, p = 0.34). Recurrent malaria infections occurred in ten (19%) children. The HRP2 and LDH-based RDTs did not detect eight and two of the recurrent infections, respectively.. The LDH-based RDT was superior to HRP2-based for monitoring of treatment outcome and detection of recurrent infections after ACT in this moderately high transmission setting. The results may have implications for the choice of RDT devices in similar transmission settings for improved malaria case management.. Clinicaltrials.gov, NCT01843764.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Diagnostic Tests, Routine; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Immunoassay; Infant; Malaria, Falciparum; Male; Microscopy; Parasitemia; Plasmodium falciparum; Real-Time Polymerase Chain Reaction; Recurrence; Tanzania

Quinine was the main treatment for malaria between 1630 and the beginning of the XXth century. In the 1940s, the synthesis of chloroquine gave rise to the hope of eliminating this plague. Falciparum resistance to chloroquine, first observed in Asia then in sub-Saharan Africa, lead researchers to discover halofantrine, mefloquine, atovaquone-proguanil and artemisinin combined therapies. There is no ideal treatment for uncomplicated imported malaria in children. Medical teams have to develop a protocol according to available drugs and their personal experience, with a special attention to follow-up at days 3-4 and day 28. From now on, severe malaria must be treated with intravenous artesunate, a more effective therapy than quinine.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Atovaquone; Child; Drug Combinations; Ethanolamines; Fluorenes; France; Humans; Malaria, Falciparum; Proguanil; Quinolines

Malaria affecting almost half of the world population continues to be an important health problem. Although domestic malaria cases have been decreasing in Turkey recently, cases caused by Plasmodium falciparum have increased due to the frequent travelling to Africa. The aims of this study were to evaluate demographic characteristics, clinical and laboratory findings in cases with falciparum malaria who attended to our clinic in 2012-2013 period, and the impact of polymerase chain reaction (PCR) for diagnosis. Nine patients evaluated were all male with a mean age of 34.3 (age range: 18-48) years, with the history of travel to Africa. Six cases did not take prophylaxis against malaria and other three cases used insufficient time. Mean duration of symptoms after return was 18.4 (range: 1-75) days, and the patients were admitted to the clinic within a mean of 5.2 (range: 1-15) days. Two patients had leucopenia, two patients had anemia, and eight patients had thrombocytopenia on admission. Alanine aminotransferase (ALT) levels in four cases and total bilirubin levels of six cases were over upper normal limits. Definitive diagnosis of cases was performed with the detection of ring and/or gametocytes forms of the parasite in Giemsa-stained peripheral blood smears. Furthermore, samples from seven patients were studied by nested PCR by using genus (Plasmodium rPLU 1 and 5) and species (rFAL 1 and 2, rVIV 1 and 2, rMAL 1 and 2, rOVA 1 and 2) specific primers. All of these seven samples yielded positive results with primers specific for P.falciparum ssrRNA. In the treatment, arthemeter/lumefantrin and doxycycline combination was used in seven patients, while intravenous artesunate and doxycycline combination was given to two patients, resulting with complete cure. Mean duration for the resolving of fever was 3.3 days, and mean duration for clearing the parasitemia from peripheral blood was 4.9 days. Initial ALT values and the duration of fever resolution (-796; p= 0.010), as well as the duration of parasitemia and initial thrombocyte counts (-797; p= 0.010) were negatively- correlated. It was concluded that, providing sufficient information on malaria and prophylaxis to people travelling to the endemic areas are crutial for protection. Moreover, in endemic areas for Crimean-Congo hemorrhagic fever, patients with fever and thrombocytopenia should be questioned in detail about the travel history, and peripheral blood smears should be examined in terms of malaria, sinc

Topics: Adolescent; Adult; Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Doxycycline; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Polymerase Chain Reaction; Travel; Turkey; Young Adult

The emerging resistance to artemisinin derivatives that has been reported in South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first line therapy for uncomplicated Plasmodium falciparum infections in Suriname. This drug assessment was performed according to the recommendations of the World Health Organization in 2011. The decreasing number of malaria cases in Suriname, which are currently limited to migrating populations and gold miners, precludes any conclusions on artemether efficacy because adequate numbers of patients with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3 parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the emergence of resistance to artemether. The prevalence of day 3 parasitaemia was assessed in a study in 2011 and was compared to that in a study in 2005/2006. The same protocol was used in both studies and artemether-lumefantrine was the study drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3 compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable patients in the 2011 study who were followed up until day 28 had negative slides and similar findings were obtained in all 38 evaluable patients in the 2005/2006 study. The significantly increased incidence of parasite persistence on day 3 may be an indication of emerging resistance to artemether.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Incidence; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Suriname; Young Adult

Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P ≤ 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246 haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased use of CQ and large-scale use of AL. In the absence of a clear AL-resistance marker and the (almost) continent-wide use of AL in sub-Saharan Africa, and when considering CQ reintroduction, continued monitoring of these markers is needed.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; DNA, Protozoan; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Haplotypes; Humans; Malaria, Falciparum; Membrane Transport Proteins; Mozambique; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Selection, Genetic; Time Factors

Tanzania adopted artemether-lumefantrine (AL) as first-line drug for uncomplicated malaria in 2006. Recently, there was an anecdotal report on high malaria recurrence rate following AL treatment in in the (urban and peri-urban), western part of Tanzania. The current report is an exploratory study to carefully and systematically assess AL efficacy in the area.. Between June and August 2011, a total of 1,126 patients were screened for malaria, 33 had malaria, of which 20 patients met inclusion criteria and were enrolled and treated with standard dose of AL as recommended in the WHO protocol. Treated patients were followed up for 28 days to assess treatment responses. Before treatment (Day 0) and post-treatment (Day 7) plasma lumefantrine levels were determined to assess prior AL use and ascertain parasites exposure to adequate plasma leveles of lumefantrine, respectively.. The cure rate was 100%. All Day 0 plasma lumefantrine were below HPLC detectable level. The median Day 7 lumefantrine concentration was 404, (range, 189-894 ng/ml). Six out of 20 patients (30%) were gametocytaemic and all cleared gametocytes by Day 14. One patient showed an increase in gametocytes from four on Day 0 to 68, per 500 WBC on Day 2.. Artemether lumefantrine is highly efficacious against uncomplicated Plasmodium falciparum malaria. The elevation of gametocytaemia despite AL treatment needs to be evaluated in a larger study.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Chromatography, High Pressure Liquid; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Plasma; Tanzania; Treatment Outcome

Correct and reliable microscopic examination results are vital in appropriate treatment of malaria in endemic areas, mainly where Plasmodiumn falciparum and P. vivax co-exist in Ethiopia. Thus, evaluation of regular malaria microscopy performance is needed.. To evaluate the performance of regular malaria microscopy and antimalarial drug prescription practices for self presenting febrile patients at health facilities located in malaria endemic areas of upper Awash Valley, eastern central Ethiopia.. A cross sectional study design was used to recruit 260 febrile patients at four health facilities in Fentale district. All slides collected at health facilities were rechecked in reference laboratories and Kappa score was calculated to see the slide reading agreement.. Malaria parasites from clinical cases were found in 19.6% (51/260) of the total febrile patients of which 82.4% (42/51) were infected with P. vivax and 17.6% (9/51) with P. falciparum. Overall sensitivity, specificity, positive and negative predictive values of regular malaria microscopy readings were 92.2%, 83.7%, 58% and 97.8%, respectively. Artemether-lumefantrine over prescription rates was 50.8% by the regular microscopy and 53.6% by reference microscopy. There was only a moderate agreement between regular malaria microscopy and reference microscopy with the Kappa value of 0.52.. The overall reading agreement and agreement on species identification of the regular and reference microscopy were low. There was variability in performance in the different health facilities. Sensitivity, specificity, and positive predictive value of regular malaria microscopy need to be improved for accurate diagnosis and prompt treatment of malaria cases in Fentale district health facilities. There should be rational use of antimalarials especially on slide negative subjects.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Health Facilities; Humans; Inappropriate Prescribing; Infant; Laboratory Proficiency Testing; Malaria, Falciparum; Malaria, Vivax; Male; Microscopy; Middle Aged; Predictive Value of Tests; Young Adult

A follow-up study was conducted to determine the magnitude of and factors related to adherence to artemether/lumefantrine (ALu) treatment in rural settings in Tanzania. Children in five villages of Kilosa District treated at health facilities were followed-up at their homes on Day 7 after the first dose of ALu. For those found to be positive using a rapid diagnostic test for malaria and treated with ALu, their caretakers were interviewed on drug administration habits. In addition, capillary blood samples were collected on Day 7 to determine lumefantrine concentrations. The majority of children (392/444; 88.3%) were reported to have received all doses, in time. Non-adherence was due to untimeliness rather than missing doses and was highest for the last two doses. No significant difference was found between blood lumefantrine concentrations among adherent (median 286 nmol/l) and non-adherent [median 261 nmol/l; range 25 nmol/l (limit of quantification) to 9318 nmol/l]. Children from less poor households were more likely to adhere to therapy than the poor [odds ratio (OR)=2.45, 95% CI 1.35-4.45; adjusted OR=2.23, 95% CI 1.20-4.13]. The high reported rate of adherence to ALu in rural areas is encouraging and needs to be preserved to reduce the risk of emergence of resistant strains. The age-based dosage schedule and lack of adherence to ALu treatment guidelines by health facility staff may explain both the huge variability in observed lumefantrine concentrations and the lack of difference in concentrations between the two groups.

Topics: Analysis of Variance; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cluster Analysis; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Medication Adherence; Odds Ratio; Risk Factors; Rural Health; Socioeconomic Factors; Tanzania

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area.

Topics: Aminoquinolines; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Evolution, Molecular; Fluorenes; French Guiana; Gene Dosage; Haplotypes; Humans; Inhibitory Concentration 50; Longitudinal Studies; Malaria, Falciparum; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Phenanthrenes; Plasmodium falciparum; Practice Guidelines as Topic; Protozoan Proteins; Quinine

Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2-based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0-59.2%) and 99.6% (95% CI = 97.7-100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7-54.9%) and 100% (95% CI = 98.3-100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed.

Topics: Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Diagnostic Tests, Routine; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications, Parasitic; Protozoan Proteins; Quinine; Sensitivity and Specificity; Species Specificity; Treatment Outcome; Uganda

Priority setting for artemisinin-based antimalarial drugs has become an integral part of malaria treatment policy change in malaria-endemic countries. Although these drugs are more efficacious, they are also more costly than the failing drugs. When Tanzania changed its National Malaria Treatment Policy in 2006, priority setting was an inevitable challenge. Artemether-lumefantrine was prioritised as the first-line drug for the management of uncomplicated malaria to be available at a subsidized price at public and faith-based healthcare facilities.. This paper describes the priority-setting process, which involved the selection of a new first-line antimalarial drug in the implementation of artemisinin-based combination therapy policy. These descriptions were further evaluated against the four conditions of the accountability for reasonableness framework. According to this framework, fair decisions must satisfy a set of publicity, relevance, appeals, and revision and enforcement conditions.In-depth interviews were held with key informants using pretested interview guides, supplemented with a review of the treatment guideline. Purposeful sampling was used in order to explore the perceptions of people with different backgrounds and perspectives. The analysis followed an editing organising style.. Publicity: The selection decision of artemether-lumefantrine but not the rationale behind it was publicised through radio, television, and newspaper channels in the national language, Swahili.. The decision was grounded on evidences of clinical efficacy, safety, affordability, and formulation profile. Stakeholders were not adequately involved. There was neither an appeals mechanism to challenge the decision nor enforcement mechanisms to guarantee fairness of the decision outcomes.. The priority-setting decision to use artemether-lumefantrine as the first-line antimalarial drug failed to satisfy the four conditions of the accountability for reasonableness framework. In our understanding, this is the first study to evaluate priority-setting decisions for new drugs in Tanzania against the accountability for reasonableness framework. In addition to the demand for enhanced stakeholder involvement, publicity, and transparency, the study also calls for the institution of formal appeals, revision, and regulatory mechanisms in the future change of malaria treatment policies.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cost-Benefit Analysis; Data Collection; Drug Combinations; Drug Industry; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Health Priorities; Humans; Malaria, Falciparum; Sample Size; Social Responsibility; Tanzania; Treatment Outcome

Increasing affordability of artemisinin combination therapy (ACT) in the African retail sector could be critical to expanding access to effective malaria treatment, but must be balanced by efforts to protect the efficacy of these drugs. Previous research estimates ACT adherence rates among public sector patients, but adherence among retail sector purchasers could differ substantially. This study aimed to estimate adherence rates to subsidized, over-the-counter ACT in rural Uganda.. An intervention study was conducted with four licensed drug shops in Eastern Uganda in December 2009. Artemether-lumefantrine (AL) was made available for sale at a 95% subsidy over-the counter. Customers completed a brief survey at the time of purchase and then were randomly assigned to one of three study arms: no follow-up, follow-up after two days or follow-up after three days. Surveyors recorded the number of pills remaining through blister pack observation or through self-report if the pack was unavailable. The purpose of the three-day follow-up arm was to capture non-adherence in the sense of an incomplete treatment course ("under-dosing"). The purpose of the two-day follow-up arm was to capture whether participants completed the full course too soon ("over-dosing").. Of the 106 patients in the two-day follow-up sample, 14 (13.2%) had finished the entire treatment course by the second day. Of the 152 patients in the three-day follow-up sample, 49 (32.2%) were definitely non-adherent, three (2%) were probably non-adherent and 100 (65.8%) were probably adherent. Among the 52 who were non-adherent, 31 (59.6%) had more than a full day of treatment remaining.. Overall, adherence to subsidized ACT purchased over-the-counter was found to be moderate. Further, a non-trivial fraction of those who complete treatment are taking the full course too quickly. Strategies to increase adherence in the retail sector are needed in the context of increasing availability and affordability of ACT in this sector.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Patient Compliance; Pharmacies; Plasmodium falciparum; Random Allocation; Uganda

Intravenous (i.v.) artesunate is now the recommended first-line treatment of severe falciparum malaria in adults and children by WHO guidelines. Nevertheless, several cases of haemolytic anaemia due to i.v. artesunate treatment have been reported. This paper describes the case of an HIV-infected patient with severe falciparum malaria who was diagnosed with haemolytic anaemia after treatment with oral artemether-lumefantrine.The patient presented with fever, headache, and arthromyalgia after returning from Central African Republic where he had been working. The blood examination revealed acute renal failure, thrombocytopaenia and hypoxia. Blood for malaria parasites indicated hyperparasitaemia (6%) and Plasmodium falciparum infection was confirmed by nested-PCR. Severe malaria according to the laboratory WHO criteria was diagnosed. A treatment with quinine and doxycycline for the first 12 hours was initially administered, followed by arthemeter/lumefantrine (Riamet(®)) for a further three days. At day 10, a diagnosis of severe haemolytic anaemia was made (Hb 6.9 g/dl, LDH 2071 U/l). Hereditary and autoimmune disorders and other infections were excluded through bone marrow aspiration, total body TC scan and a wide panel of molecular and serologic assays. The patient was treated by transfusion of six units of packed blood red cell. He was discharged after complete remission at day 25. At present, the patient is in a good clinical condition and there is no evidence of haemolytic anaemia recurrence.This is the first report of haemolytic anaemia probably associated with oral artemether/lumefantrine. Further research is warranted to better define the adverse events occurring during combination therapy with artemisinin derivatives.

Topics: Administration, Oral; Adult; Anemia, Hemolytic; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Coinfection; Drug Combinations; Drug Therapy, Combination; Erythrocytes; Ethanolamines; Fluorenes; Hemolysis; HIV; HIV Infections; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Severity of Illness Index

The adoption of artemisinin-based combination therapy, together with other malaria control strategies, has played a significant role in reducing the burden of malaria in many endemic countries. The artemisinin-based combination therapy artemether-lumefantrine (AL; Coartem(®), Novartis Pharma AG, Basel, Switzerland) has demonstrated consistently high efficacy and safety for over a decade. Currently deployed as a first- or second-line treatment in most sub-Saharan African countries, its extensive use is endorsed by a lack of reported parasite resistance in Africa to date. With a focus on patient needs, AL offers a tailored formulation for infants and children, and packaging solutions to promote adherence. Working towards malaria elimination, innovative strategies using AL, such as treatment of asymptomatic carriers, will be of interest. AL has the potential to continue playing an important role in saving lives.

Topics: Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Disease Management; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Randomized Controlled Trials as Topic; Treatment Outcome

Artemether-lumefantrine is currently first-line therapy of Plasmodium falciparum malaria in many countries. This report describes a treatment failure despite adequate drug concentrations in a traveller returning from sub-Saharan Africa. Genotyping confirmed recrudescence and suggested reduced sensitivity. Potential sub-optimal effect of artemether-lumefantrine highlights the need to follow non-immune individuals the weeks after treatment.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Genotype; Humans; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Recurrence; Tanzania; Travel; Treatment Failure

The Lao Government changed the national policy for uncomplicated Plasmodium falciparum malaria from chloroquine to artemether-lumefantrine (AL) in 2005. Since then, no information on AL efficacy has been reported. With evidence of resistance to artemisinin derivatives in adjacent Cambodia, there has been a concern as to AL efficacy. Monitoring of AL efficacy would help the Lao Government to make decisions on appropriate malaria treatment.. The efficacy of a three-day, twice daily oral artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Xepon District, Savannakhet Province, southern Laos was studied over 42 days follow-up. This was part of a trial of thiamin supplementation in falciparum malaria.. Of 630 patients with P. falciparum enrolled in the trial of thiamin treatment, 549 (87%, 357 children ≤15 years and 192 adults) were included in this study. The per protocol 42-day cure rates were 97% (524/541) [96% (337/352) for children and 99% (187/189) for adults, p = 0.042]. By conventional intention-to-treat analysis, the 42-day cure rates adjusted for re-infection, were 97% (532/549) [96% (342/357) in children and 99% (190/192) in adults, p = 0.042]. The proportion of patients who remained parasitaemic at day 1 after treatment was significantly higher in children [33% (116/356)] compared to adults [15% (28/192)] (p < 0.001) and only one adult patient had detectable parasitaemia on day 2. There were no serious adverse events. Potential side effects after treatment were reported more commonly in adults (32%) compared to children (15%) (p < 0.001). Patients with recrudescent infections were significantly younger, had longer mean time to fever clearance, and had longer median time to parasite clearance compared to those who were cured.. The current nationally-recommended anti-malarial treatment (artemether-lumefantrine) remains highly efficacious for the treatment of uncomplicated falciparum malaria five years after introduction in Laos. Regular monitoring is required in case artemisinin-resistant P. falciparum parasites should appear.. ISRCTN85411059.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Laos; Malaria, Falciparum; Male; Middle Aged; Treatment Outcome; Young Adult

To measure maternal and fetal hemodynamics during acute malaria in pregnancy.. Time courses of maternal heart rate (MHR), maternal blood pressure (BP), and fetal heart rate (FHR) were performed until 56 days after initiation of anti-malarial treatment with artemether-lumefantrine. Women with malaria were hospitalized for at least 3 days until recovery.. Mean baseline characteristics of pregnant women with malaria (n=38) versus pregnant women without malaria (n=39) were as follows: gestational age (28.8 vs 24.6 weeks; P=0.006); maximum FHR (165.3 vs 158.3 beats per minute [bpm]; P=0.054); minimum FHR (137.6 vs 128.7 bpm; P=0.016); mean BP (74.7 vs 80.9 mm Hg; P=0.001); pulse pressure (40.3 vs 42.1mm Hg; P=0.300); and MHR (107.4 vs 81.3 bpm; P<0.001). The geometric mean parasite count was 13 795 per μL. Complete time courses were collected from a subgroup of participants. For women with malaria, maternal body temperature and BP normalized within 24 hours and after 72 hours, respectively. The MHR among pregnant women without malaria showed a physiologic increase during pregnancy of approximately 7 bpm between days 0 and 56. The mean FHR among women with malaria normalized after 72 hours.. Acute malaria induces maternal and fetal hemodynamic changes.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Temperature; Drug Combinations; Ethanolamines; Female; Fluorenes; Hemodynamics; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Young Adult

Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed.. Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach.. The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous).. This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Dose-Response Relationship, Drug; Drug Combinations; Drug Discovery; Ethanolamines; Fluorenes; Host-Pathogen Interactions; Humans; Malaria, Falciparum; Mefloquine; Models, Statistical; Plasmodium falciparum; Quinolines

Malaria remains a major public health problem in Togo. The national malaria control programme in Togo changed the anti-malarial treatment policy from monotherapy to artemisinin combination therapy in 2004. This study reports the results of therapeutic efficacy studies conducted on artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Togo, between 2005 and 2009.. Children between 6 and 59 months of age, who were symptomatically infected with P. falciparum, were treated with either artemether-lumefantrine or artesunate-amodiaquine. The primary end-point was the 28-day cure rate, PCR-corrected for reinfection and recrudescence. Studies were conducted according to the standardized WHO protocol for the assessment of the efficacy of anti-malarial treatment. Differences between categorical data were compared using the chi-square test or the Fisher's exact test where cell counts were ≤ 5. Differences in continuous data were compared using a t-test.. A total of 16 studies were conducted in five sentinel sites, with 459, 505 and 332 children included in 2005, 2007 and 2009, respectively. The PCR-corrected 28-day cure rates using the per-protocol analysis were between 96%-100% for artemether-lumefantrine and 94%-100% for artesunate-amodiaquine.. Both formulations of artemisinin-based combination therapy were effective over time and no severe adverse events related to the treatment were reported during the studies.

Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; DNA, Protozoan; Drug Combinations; Ethanolamines; Female; Fluorenes; Genotype; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction; Togo; Treatment Outcome

Recent malaria epidemics in KwaZulu-Natal indicate that effective anti-malarial therapy is essential for malaria control. Although artemether-lumefantrine has been used as first-line treatment for uncomplicated Plasmodium falciparum malaria in northern KwaZulu-Natal since 2001, its efficacy has not been assessed since 2002. The objectives of this study were to quantify the proportion of patients treated for uncomplicated P. falciparum malaria with artemether-lumefantrine who failed treatment after 28 days, and to determine the prevalence of molecular markers associated with artemether-lumefantrine and chloroquine resistance.. An observational cohort of 49 symptomatic patients, diagnosed with uncomplicated P. falciparum malaria by rapid diagnostic test, had blood taken for malaria blood films and P. falciparum DNA polymerase chain reaction (PCR). Following diagnosis, patients were treated with artemether-lumefantrine (Coartem®) and invited to return to the health facility after 28 days for repeat blood film and PCR. All PCR P. falciparum positive samples were analysed for molecular markers of lumefantrine and chloroquine resistance.. Of 49 patients recruited on the basis of a positive rapid diagnostic test, only 16 were confirmed to have P. falciparum by PCR. At follow-up, 14 were PCR-negative for malaria, one was lost to follow-up and one blood specimen had insufficient blood for a PCR analysis. All 16 with PCR-confirmed malaria carried a single copy of the multi-drug resistant (mdr1) gene, and the wild type asparagine allele mdr1 codon 86 (mdr1 86N). Ten of the 16 samples carried the wild type haplotype (CVMNK) at codons 72-76 of the chloroquine resistance transporter gene (pfcrt); three samples carried the resistant CVIET allele; one carried both the resistant and wild type, and in two samples the allele could not be analysed.. The absence of mdr1 gene copy number variation detected in this study suggests lumefantrine resistance has yet to emerge in KwaZulu-Natal. In addition, data from this investigation implies the possible re-emergence of chloroquine-sensitive parasites. Results from this study must be viewed with caution, given the extremely small sample size. A larger study is needed to accurately determine therapeutic efficacy of artemether-lumefantrine and resistance marker prevalence. The high proportion of rapid diagnostic test false-positive results requires further investigation.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cohort Studies; Drug Combinations; Drug Resistance; Ethanolamines; Female; Fluorenes; Gene Dosage; Genes, Protozoan; Humans; Malaria, Falciparum; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymerase Chain Reaction; South Africa; Treatment Outcome; Young Adult

Improvements in availability and accessibility of artemisinin-based combination therapy (ACT) for malaria treatment and the emergence of multi-drug-resistant parasites have prompted many countries to adopt ACT as the first-line drug. In 2009, Solomon Islands (SI) likewise implemented new national treatment guidelines for malaria. The ACT, Coartem® (artemether-lumefantrine) is now the primary pharmacotherapy in SI for Plasmodium falciparum malaria, Plasmodium vivax malaria or mixed infections. Targeted treatment is also recommended in the new treatment regime through maintenance of quality microscopy services and the introduction of Rapid Diagnostic Tests (RDTs). Ascertaining the factors that influence community and provider acceptance of and adherence to the new treatment regime will be vital to improving the effectiveness of this intervention and reducing the risk of development of drug resistance.. In order to understand community and prescriber perceptions and acceptability of the new diagnostic and treatment interventions, 12 focus group discussions (FGDs) and 12 key informant interviews (KII) were carried out in rural and urban villages of Malaita Province, Solomon Islands four months subsequent to roll out of these interventions.. Lack of access to microscopy or distrust in the accuracy of diagnostic tools were reported by some participants as reasons for the ongoing practice of presumptive treatment of malaria. Lack of confidence in RDT accuracy has negatively impacted its acceptability. Coartem® had good acceptability among most participants, however, some rural participants questioned its effectiveness due to lack of side effects and the larger quantity of tablets required to be taken. Storing of left over medication for subsequent fever episodes was reported as common.. To address these issues, further training and supportive supervision of healthcare workers will be essential, as will the engagement of influential community members in health promotion activities to improve acceptability of RDTs and adherence to the new treatment regime. Exploring the extent of these issues beyond the study population must be a priority for malaria programme managers. Practices such as presumptive treatment and the taking of sub-curative doses are of considerable concern for both the health of individuals and the increased risk it poses to the development of parasite resistance to this important first-line treatment against malaria.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Female; Fluorenes; Guideline Adherence; Humans; Interviews as Topic; Malaria, Falciparum; Malaria, Vivax; Male; Melanesia; Middle Aged; Patient Acceptance of Health Care; Rural Population; Urban Population; Young Adult

Despite global antimalarial measures, Plasmodium falciparum malaria remains a major public health problem. WHO has recommended the use of arteminisin-based combination therapy to limit the emergence of antimalarial drug resistance. However, ACT treatment failures have been linked to the selection of the wild types 86N genotype of P. falciparum multidrug resistance 1 (Pfmdr1) and the 76K genotype of P. falciparum chloroquine resistance (Pfcrt) genes. The aim of this study was to investigate the molecular impact of widespread implementation of artemether-lumefantrine and artesunate-mefloquine on local parasite population in Franceville, Gabon. We analyzed 230 pediatric field isolates (96 from 2004 and 134 from 2009). Routine hematological parameters were collected. Pfmdr1 codons 86 and 1246 and Pfcrt codon 76 were genotyped using PCR-RFLP and the prevalence of the genotypes was compared. The children's mean age did not differ between 2004 and 2009 (respectively 31.8 (6-84) months vs 38.6 (6-84) months, p=0.32), and neither did mean parasitemia [16,750 (1000-96,234) and 14,587 (1093-83,941) parasites/μL, respectively (p=0.21)]. The mean hemoglobin level was higher in 2009 than in 2004 (11.0 ± 2.4 vs 7.8 ± 2.0 g/dL, respectively; p=0.04). More interesting, the prevalence of Pfmdr1 wild type 86N increased from 15.6% (n=15/96) in 2004 to 31.3% (n=42/134) in 2009 (p=0.007). A significant increase combining pure and mixed genotypes (86N+86N/Y) was also found between 2004 and 2009 (p=0.02), while the prevalence of genotypes Pfmdr1 1246D, Pfcrt wild type 76T and all mixed genotypes (Pfmdr1 86N/Y and 1246D/Y, and 76K/T) remained stable. The complexity of isolates was high (around 2.9 and 2.4) and the FC27 allele of Pfmsp2 was more prevalent. These findings show a substantial benefice of artemether-lumefantrine and artesunate-mefloquine and of new control measures. The selection, in the general population, of wild type Pfmdr1 86N, which is associated with antiplasmodial resistance against some drugs, has been induced underlining the need for molecular surveillance of the impact of ACT on antimalarial resistance.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Chloroquine; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Gabon; Genotype; Humans; Infant; Malaria, Falciparum; Male; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitemia; Plasmodium falciparum; Polymorphism, Genetic; Prevalence; Protozoan Proteins

To assess the in vivo efficacy and adverse effects of Artemether-lumefantrine combination in acute uncomplicated falciparum malaria.. A prospective, observational study was conducted at Department of Medicine and Pathology, Pakistan Medical level II hospital, Tubmanburg and Harper from March 2009 to September 2009. One hundred subjects with positive Plasmodium falciparum rings on malaria slide fulfilled the selection criteria and were included in the study. Mean, minimum and maximum values along with standard deviation of age, malarial parasite index, fever clearance time and parasite clearance time were calculated. A 28 day parasitological cure rate was determined. Frequency of various adverse events observed during this study were also noted.. Of 100 subjects, 70 wereAfricans while remaining were Asians. Mean fever clearance time in Africans and Asians were 18.9 +/- 11.5 and 27.9 +/- 14.3 hours respectively. The mean parasite clearance time was almost similar in both races ranging from 28 to 31 hours. A 28 day parasitological cure rate was found to be 100%. About 10% of the subjects developed mild to moderate side effects including headache, vomiting, loss of sleep, vertigo and diarrhoea. There was no mortality during the study.. Artemether Lumefantrine combination therapy may be used safely and effectively in the management of acute uncomplicated falciparum malaria.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fever; Fluorenes; Humans; Infant; Liberia; Malaria, Falciparum; Male; Plasmodium falciparum; Prospective Studies; Treatment Outcome; Young Adult

The therapeutic efficacies of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine during 5 years of adoption as first-line treatments were evaluated in 811 ≤ 12-year-old malarious children. Compared with artemether-lumefantrine, amodiaquine-artesunate significantly reduced the proportion of children with fever and parasitemia 1 day after treatment (day 1; P < 0.008 for both). The proportion of parasitemic children on day 2 and gametocytemia on presentation and carriage reduced significantly over the years (P < 0.000001 and P < 0.03, respectively; test for trend). Overall efficacy was 96.5% (95% confidence interval [CI] = 94.5-98.6) and remained unchanged over the years (P = 0.87; test for trend). Kinetics of parasitemias after treatments were estimated by a non-compartmental model. Declines of parasitemias were monoexponential, with a mean elimination half-life of 1.09 hours (95% CI = 1.0-1.16). Parasitemia half-lives and efficacy were similar for both regimens and in all ages. Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated falciparum malaria in Nigerian children 5 years after adoption.

Topics: Amodiaquine; Analysis of Variance; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Half-Life; Humans; Infant; Malaria, Falciparum; Male; Nigeria; Parasitemia; Plasmodium falciparum; Prospective Studies; Randomized Controlled Trials as Topic; Treatment Outcome

Asymptomatic carriers of Plasmodium falciparum serve as a reservoir of parasites for malaria transmission. Identification and treatment of asymptomatic carriers within a region may reduce the parasite reservoir and influence malaria transmission in that area.. Using computer simulation, this analysis explored the impact of community screening campaigns (CSC) followed by systematic treatment of P. falciparum asymptomatic carriers (AC) with artemether-lumefantrine (AL) on disease transmission. The model created by Okell et al (originally designed to explore the impact of the introduction of treatment with artemisinin-based combination therapy on malaria endemicity) was modified to represent CSC and treatment of AC with AL, with the addition of malaria vector seasonality. The age grouping, relative distribution of age in a region, and degree of heterogeneity in disease transmission were maintained. The number and frequency of CSC and their relative timing were explored in terms of their effect on malaria incidence. A sensitivity analysis was conducted to determine the factors with the greatest impact on the model predictions.. The simulation showed that the intervention that had the largest effect was performed in an area with high endemicity (entomological inoculation rate, EIR > 200); however, the rate of infection returned to its normal level in the subsequent year, unless the intervention was repeated. In areas with low disease burden (EIR < 10), the reduction was sustained for over three years after a single intervention. Three CSC scheduled in close succession (monthly intervals) at the start of the dry season had the greatest impact on the success of the intervention.. Community screening and treatment of asymptomatic carriers with AL may reduce malaria transmission significantly. The initial level of disease intensity has the greatest impact on the potential magnitude and duration of malaria reduction. When combined with other interventions (e.g. long-lasting insecticide-treated nets, rapid diagnostic tests, prompt diagnosis and treatment, and, where appropriate, indoor residual spraying) the effect of this intervention can be sustained for many years, and it could become a tool to accelerate the reduction in transmission intensity to pre-elimination levels. Repeated interventions at least every other year may help to prolong the effect. The use of an effective diagnostic tool and a highly effective ACT, such as AL, is also vital. The modelling supports the evaluation of this approach in a prospective clinical trial to reduce the pool of infective vectors for malaria transmission in an area with marked seasonality.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Asymptomatic Diseases; Child; Child, Preschool; Communicable Disease Control; Computer Simulation; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Mass Screening; Middle Aged; Models, Statistical; Parasitology; Young Adult

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cell Phone; Drug Combinations; Ethanolamines; Fluorenes; Guideline Adherence; Health Personnel; Humans; Kenya; Malaria, Falciparum; Reminder Systems; Rural Health Services

We compared the prevalence of key pfmdr1 alleles between pretreatment Plasmodium falciparum parasite isolates and parasites that emerged after treatment of uncomplicated malaria in a longitudinal cohort of Ugandan children. The pfmdr1 86N, 184F, and 1246D alleles were selected after treatment with artemether-lumefantrine, but not after artesunate-amodiaquine or amodiaquine-sulfadoxine-pyrimethamine. Remarkably, selection persisted in infections presenting up to about 60 days after treatment with artemether-lumefantrine. Thus, parasites selected for decreased drug sensitivity can appear long after predicted exposure to antimalarial drugs. Continued surveillance of the clinical efficacy and in vitro activity of new combination therapies is warranted.

Topics: Alleles; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Longitudinal Studies; Malaria, Falciparum; Male; Plasmodium falciparum; Polymorphism, Genetic; Pyrimethamine; Sulfadoxine; Time Factors; Uganda

In 2004, Ethiopia switched its first-line treatment of uncomplicated Plasmodium falciparum malaria from sulphadoxine-pyrimethamine to a fixed artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL). Patient adherence to AL regimen is a major determining factor to achieve the desired therapeutic outcome. The aim of this study was to measure patient adherence levels to the six-dose AL regimen for the treatment of uncomplicated P. falciparum malaria and to identify its determinant factors in rural areas of the Tigray region, Ethiopia. The study was conducted under routine health service delivery at health posts level. Patients/caregivers were not informed about their home visit and were traced on the day after they finished the AL regimen. By combining the response to a structured questionnaire and the tablet count from the blister, adherence level was classified into three categories: definitely non-adherent, probably non-adherent and probably adherent. Reasons for being definitely non-adherent were also assessed. For the purpose of examine risk factors, definitely non-adherent and probably non-adherent was merged into a non-adherent group. Variables found significantly associated (p < 0.05) with the adherence level on the univariate analysis were fitted into a multivariate logistic regression model.. Out of the total initially enrolled 180 patients, 86.1% completed the follow-up. Out of these, 38.7% were classified as probably adherent, 34.8% as probably non-adherent, and 26.5% were definitely non-adherent. The most common reasons that definitely non-adherents gave for not taking the full dose were "too many tablets" (37.3%) and to "felt better before finished the treatment course" (25.5%). The adherence of the patients was associated with the ownership of a radio (adjusted odd ratio, AOR: 3.8; 95% CI: 1.66-8.75), the belief that malaria can be treated traditionally (AOR: 0.09; 95% CI: 0.01-0.78) and a delay of more than one day in seeking treatment after the onset of fever (AOR: 5.39; 95% CI: 1.83-15.88).. The very low adherence to AL found in this study raises serious concerns for the malaria control in the region. The implementation of a monitoring adherence system is essential to ensure long-term treatment efficacy.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Male; Medication Adherence; Rural Population; Surveys and Questionnaires; Young Adult

Increased investment and commitment to malaria prevention and treatment strategies across Africa has produced impressive reductions in the incidence of this disease. Nevertheless, it is clear that further interventions will be necessary to meet the international target of a reversal in the incidence of malaria by 2015. This article discusses the prospective role of an innovative malaria control strategy - the community-based treatment of asymptomatic carriers of Plasmodium falciparum, with artemisinin-based combination therapy (ACT). The potential of this intervention was considered by key scientists in the field at an Advisory Board meeting held in Basel, in April 2009. This article summarizes the discussions that took place among the participants.. Asymptomatic carriers do not seek treatment for their infection and, therefore, constitute a reservoir of parasites and thus a real public-health risk. The systematic identification and treatment of individuals with asymptomatic P. falciparum as part of a surveillance intervention strategy should reduce the parasite reservoir, and if this pool is greatly reduced, it will impact disease transmission.. This article considers the populations that could benefit from such a strategy and examines the ethical issues associated with the treatment of apparently healthy individuals, who represent a neglected public health risk. The potential for the treatment of asymptomatic carriers to impair the development of protective immunity, resulting in a 'rebound' and age escalation of malaria incidence, is also discussed.For policymakers to consider the treatment of asymptomatic carriers with ACT as a new tool in their malaria control programmes, it will be important to demonstrate that such a strategy can produce significant benefits, without having a negative impact on the efficacy of ACT and the health of the target population.. The treatment of asymptomatic carriers with ACT is an innovative and essential tool for breaking the cycle of infection in some transmission settings. Safe and effective medicines can save the lives of children, but the reprieve is only temporary so long as the mosquitoes can become re-infected from the asymptomatic carriers. With improvements in rapid diagnostic tests that allow easier identification of asymptomatic carriers, the elimination of the pool of parasites is within reach.

Topics: Africa South of the Sahara; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Carrier State; Cost of Illness; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Incidence; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Population Surveillance; Prevalence; Risk; Treatment Outcome

New malaria treatment guidelines in Tanzania have led to the large-scale deployment of artemether-lumefantrine (Coartem), popularly known as ALu or dawa mseto. Very little is known about how people in malaria endemic areas interpret policy makers' decision to replace existing anti-malarials, such as sulphadoxine-pyrimethamine (SP) with "new" treatment regimens, such as ALu or other formulations of ACT. This study was conducted to examine community level understandings and interpretations of ALu's efficacy and side-effects. The paper specifically examines the perceived efficacy of ALu as articulated by the mothers of young children diagnosed with malaria and prescribed ALu.. Participant observation, six focus group discussions in two large villages, followed by interviews with a random sample of 110 mothers of children less than five years of age, who were diagnosed with malaria and prescribed ALu. Additionally, observations were conducted in two village dispensaries involving interactions between mothers/caretakers and health care providers.. While more than two-thirds of the mothers had an overall negative disposition toward SP, 97.5% of them spoke favourably about ALu, emphasizing it's ability to help their children to rapidly recover from malaria, without undesirable side-effects. 62.5% of the mothers reported that they were spending less money dealing with malaria than previously when their child was treated with SP. 88% of the mothers had waited for 48 hours or more after the onset of fever before taking their child to the dispensary. Mothers' knowledge and reporting of ALu's dosage was, in many cases, inconsistent with the recommended dosage schedule for children.. Deployment of ALu has significantly changed community level perceptions of anti-malarial treatment. However, mothers continue to delay seeking care before accessing ALu, limiting the impact of highly subsidized rollout of the drug. Implementation of ACT-based treatment guidelines must be complemented with educational campaigns to insure that mothers seek prompt help for their children within 24 hours of the onset of fever. Improved communication between health care providers and mothers of sick children can facilitate better adherence to ALu's recommended dosage. Community level interpretations of anti-malarials are multifaceted; integrating knowledge of local beliefs and practices surrounding consumption of anti-malarials into programmatic goals can help to significantly improve malaria control interventions.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Community Health Services; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Focus Groups; Health Knowledge, Attitudes, Practice; Humans; Infant; Infant, Newborn; Interviews as Topic; Malaria, Falciparum; Male; Middle Aged; Mothers; Patient Acceptance of Health Care; Plasmodium; Socioeconomic Factors; Tanzania; Young Adult

There is renewed acknowledgement that targeting gametocytes is essential for malaria control and elimination efforts. Simple mathematical models were fitted to data from clinical trials in order to determine the mean gametocyte circulation time and duration of gametocyte carriage in treated malaria patients.. Data were used from clinical trials from East Africa. The first trial compared non-artemisinin combination therapy (non-ACT: sulphadoxine-pyrimethamine (SP) plus amodiaquine) and artemisinin-based combination therapy (ACT: SP plus artesunate (AS) or artemether-lumefantrine). The second trial compared ACT (SP+AS) with ACT in combination with a single dose of primaquine (ACT-PQ: SP+AS+PQ). Mature gametocytes were quantified in peripheral blood samples by nucleic acid sequence based amplification. A simple deterministic compartmental model was fitted to gametocyte densities to estimate the circulation time per gametocyte; a similar model was fitted to gametocyte prevalences to estimate the duration of gametocyte carriage after efficacious treatment.. The mean circulation time of gametocytes was 4.6-6.5 days. After non-ACT treatment, patients were estimated to carry gametocytes for an average of 55 days (95% CI 28.7 - 107.7). ACT reduced the duration of gametocyte carriage fourfold to 13.4 days (95% CI 10.2-17.5). Addition of PQ to ACT resulted in a further fourfold reduction of the duration of gametocyte carriage.. These findings confirm previous estimates of the circulation time of gametocytes, but indicate a much longer duration of (low density) gametocyte carriage after apparently successful clearance of asexual parasites. ACT shortened the period of gametocyte carriage considerably, and had the most pronounced effect on mature gametocytes when combined with PQ.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Carrier State; Child; Child, Preschool; Clinical Trials as Topic; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Germ Cells; Humans; Infant; Infant, Newborn; Kenya; Malaria, Falciparum; Male; Models, Biological; Parasitemia; Plasmodium falciparum; Prevalence; Primaquine; Pyrimethamine; Self-Sustained Sequence Replication; Sulfadoxine; Tanzania; Time Factors; Treatment Outcome

The decline in malaria coinciding with the introduction of newer, costly anti-malarials has prompted studies into the overtreatment for malaria mostly in East Africa. The study presented here describes prescribing practices for malaria at health facilities in a West African country.. Cross-sectional surveys were carried out in two urban Gambian primary health facilities (PHFs) during and outside the malaria transmission season. Facilities were comparable in terms of the staffing compliment and capability to perform slide microscopy. Patients treated for malaria were enrolled after consultations and blood smears collected and read at a reference laboratory. Slide reading results from the PHFs were compared to the reference readings and the proportion of cases treated but with a negative test result at the reference laboratory was determined.. Slide requests were made for 33.2% (173) of those enrolled, being more frequent in children (0-15 yrs) than adults during the wet season (p = 0.003). In the same period, requests were commoner in under-fives compared to older children (p = 0.022); however, a positive test result was 4.4 times more likely in the latter group (p = 0.010). Parasitaemia was confirmed for only 4.7% (10/215) and 12.5% (37/297) of patients in the dry and wet seasons, respectively. The negative predictive value of a PHF slide remained above 97% in both seasons.. The study provides evidence for considerable overtreatment for malaria in a West African setting comparable to reports from areas with similar low malaria transmission in East Africa. The data suggest that laboratory facilities may be under-used, and that adherence to negative PHF slide results could significantly reduce the degree of overtreatment. The "peak prevalence" in 5-15 year olds may reflect successful implementation of malaria control interventions in under-fives, but point out the need to extend such interventions to older children.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Female; Fluorenes; Gambia; Guideline Adherence; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Microscopy; Parasitemia; Plasmodium falciparum; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prevalence; Seasons; Sensitivity and Specificity; Urban Population

The emergence of drug resistance is a major problem in malaria control. Combination of molecular genotyping and characterization of mutations or single nucleotide polymorphisms (SNPs) correlated with drug resistance can provide information for subsequent surveillance of existing and developing drug resistance patterns. The introduction of artemether/lumefantrine (AL) as first-line treatment, never used before in Ethiopia, allowed the collection of baseline data of molecular polymorphisms before a selection due to AL could occur.. 97 patients with uncomplicated falciparum malaria were recruited from April to June 2006 and treated with either AL, quinine (Q) or atovaquone/proguanil (AP) in Jimma University Hospital, Ethiopia. Mutations or SNPs associated with resistance to these drugs were analysed by RFLP (pfdhfr, pfmdr1) and sequencing of the target genes (pfcytb, pfserca ).. SNPs previously reported to be associated with resistance to the study drugs were identified in recrudescent and treatment sensitive isolates. A total of seven recrudescences were obtained. The pfmdr1 N86Y mutation was found in 84.5% of isolates. The triple mutation 51I,59R,108N of the pfdhfr gene occured in high frequency (83.3%) but no pfcytb mutation was detected. Sequencing showed a variety of previously described and new mutations in the pfserca gene.. The prevalence of mutations was in accordance with the expected patterns considering recent drug regimens. The broad introduction of AL and the cessation of former drug regimens might probably change the current distribution of polymorphisms, possibly leading to decreased sensitivity to AL in future. Continuous surveillance of molecular patterns in this region is, therefore, recommended.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Atovaquone; Child; Cytochromes b; Drug Combinations; Drug Resistance; Ethanolamines; Ethiopia; Female; Fluorenes; Genotype; Hospitals, University; Humans; Malaria, Falciparum; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Prevalence; Proguanil; Quinine; Recurrence; Sequence Analysis, DNA; Tetrahydrofolate Dehydrogenase; Young Adult

Topics: Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Medication Adherence; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Infectious; Quinine; Randomized Controlled Trials as Topic; Treatment Outcome

Artesunate derivative drugs are newly introduced antimalaria drugs developed in response to the increasing drug resistance malaria spread.. To determine the parasitological resistance and the clinical failure to Artemether-Lumefantrin (Coartem); and artesunate plus sulfadoxine pyrimethamine (SP) by the WHO 14 day in vivo test.. The WHO 14 day in vivo efficacy study for coartem and artesunate with sulfadoxine-pyrimethamine covered the period from Nov 28 to Dec. 26, 2006 with 141 patients of ages 2 - 35 years with uncomplicated malaria around the big hydroelectric power dam region of Gilgel Gibe II (GGII). There was close clinical follow up and included parasitic load and clearance. Packed red cell volume (Hematocrit) was measured at day 0 and 14.. Parasitological resistance (RI, RII, RIII) to Coartem; and artesunate plus SP was not observed. There was no early as well as late clinical failure. All patients had adequate clinical response. The prevalence of malarial anemia (Hct < 33%) was 14.9% at day 0 and had decreased to 7.5% by day 14 in both groups.. Coartem and artesunate with SP are highly efficacious in the treatment of uncomplicated malaria in the GGII hydroelectric dam area.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Ethiopia; Female; Fever; Fluorenes; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sentinel Surveillance; Sulfadoxine; Treatment Outcome; Young Adult

We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca(2+) ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pfmdr1 haplotype 86N-184F-1246D was significantly associated (P < 0.00001) with treatment failures and was selected for among posttreatment samples obtained from patients with newly acquired or recrudescing infections (P < 0.00001; chi(2) = 36.5) and in gametocytes (log rank statistic = 5; P = 0.0253) after treatment with AL. All pre- and posttreatment samples as well as gametocytes harbored a single copy of the Pfmdr1 gene and the wild-type allele (L89) at codon 89 of the PfATPase6 gene. These findings suggest that polymorphisms in the Pfmdr1 gene are under AL selection pressure. Pfmdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa.

Topics: Alleles; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Follow-Up Studies; Gene Dosage; Genes, MDR; Haplotypes; Humans; Malaria, Falciparum; Nigeria; Plasmodium falciparum; Polymorphism, Genetic; Selection, Genetic; Time Factors; Treatment Outcome

The combination of artesunate and mefloquine was introduced as the national first-line treatment for Plasmodium falciparum malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since pfmdr1 modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between pfmdr1 copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy.. Blood samples were collected from P. falciparum-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group) in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group) in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC50 was tested and the strains were genotyped for pfmdr1 copy number by real-time PCR.. The pfmdr1 copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased pfmdr1 copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between pfmdr1 polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean pfmdr1copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p < 0.001). This was not observed in the patients treated with AL (n = 96, p = 0.364). The presence of three or more copies of pfmdr1 were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR) = 7.80 [95%CI: 2.09-29.10], N = 115), p = 0.002) but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24-4.44], N = 109, p = 0.969).. This study shows that pfmdr1 copy number is a molecular marker of AM treatment failure in falciparum malaria on the Thai-Cambodian border. However, while it is associated with increased IC50 for lumefantrine, pfmdr1 copy number is not associated with AL treatment failure in the area, suggesting involvement of other molecular mechanisms in AL treatment failures in Cambodia.

Topics: Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Cambodia; Child; Clinical Trials as Topic; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Gene Dosage; Genetic Variation; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Mefloquine; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Survival Analysis; Thailand; Treatment Failure

Artemether-lumefantrine, a tablet formulation of these respective antimalarial compounds, has been developed for the treatment of patients with drug-resistant malaria worldwide. Many studies have shown that it is most effective of the antimalarial compounds in shortening the fever and parasite clearance times. However, several treatment failures have been reported. These failures are believed to be a consequence of poor bioavailability of the lumefantrine component when ingested without fatty food. This paper reports the first case of such treatment failure of imported malaria in Japan in a 58-year-old Japanese man who showed recrudescence of Plasmodium falciparum after treatment with artemether-lumefantrine. The drug was administered to the patient in 6 doses, each time without fatty food and on a seemingly empty stomach. It is believed that treatment failure was due to poor absorption and a subsequent low plasma concentration of lumefantrine. Although artemether-lumefantrine has not been approved for use in Japan and is thus not commonly used there at present, it is thought to be the most promising drug of choice for the treatment of drug-resistant malaria. Taking an appropriate dosage and providing patients with proper instructions on taking the drug concurrently with fatty food are required for effective treatment with artemether-lumefantrine.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Asian People; Drug Combinations; Ethanolamines; Fluorenes; Humans; Japan; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Travel; Treatment Failure

We genotyped 160 P. falciparum infections from Malawi for pfmdr-1 copy number changes and SNPs associated with in vivo tolerance and poor in vitro sensitivity to the component drugs of Coartem. We also measured in vitro susceptibility of 49 of these isolates to a variety of drugs in clinical use or with a potential for use in Africa. All 160 infections carried a single copy of pfmdr-1 but 34% exhibited sequence variation at 4 of the 5 polymorphic sites in pfmdr-1. Isolates carrying 86-Asn and 184-Tyr pfmdr-1 alleles were significantly less sensitive (p<0.001) to mefloquine, lumefantrine, artemether and dihydroartemisinin compared with those bearing 86-Tyr and 184-Phe polymorphisms. This study provides baseline measures prior to policy change: continued surveillance for changes in baseline drug susceptibility, pfmdr-1 copy number and SNPs, and other putative Coartem resistance loci will be necessary to provide an early warning of emerging Coartem resistance in this setting.

Topics: Amino Acid Substitution; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Gene Dosage; Humans; Infant; Inhibitory Concentration 50; Malaria, Falciparum; Malawi; Multidrug Resistance-Associated Proteins; Mutation, Missense; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Single Nucleotide

We assessed the clinical and parasitological efficacy of six-dose regimen of artemether-lumefantrine (AL) (Coartem) for treating uncomplicated P. falciparum malaria three years after its introduction into Ethiopia. A total of 102 patients (mean age: 15.7 years; age range: 1-50 years) were enrolled in the study and followed-up for 28 days based on WHO protocol. Treatment with AL resulted in 100% adequate clinical and parasitological response (ACPR). No severe side-effect of the drug was observed. All patients had rapid clinical and parasitological responses. None of the subject was found to be positive for asexual or sexual stage of the parasite after day 3. A significant increase in the mean of haemoglobin level was observed on day 28 posttreatment (11.4 g/dL on day 0 vs 12.3 g/dL on day 28, p < 0.05). Thus, artemisinin-based combination therapies (ACTs) seem to mitigate not only the problem of drug resistance malaria but also the transmission of the disease. Nevertheless, monitoring ACT therapeutic efficacy is crucial in Ethiopia.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Treatment Outcome; Young Adult

An assessment of the accuracy of two malaria rapid diagnostic tests (RDT) for the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) or Pf lactate dehydrogenase (PfLDH) was undertaken in children aged between six and 59 months included in an anti-malarial efficacy study in Benin.. In Allada (Benin), 205 children aged 6-59 months with falciparum malaria received either artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL), or sulphadoxine-pyrimethamine (SP). Children included in the study were simultaneously followed by both RDT and high-quality microscopy for up to 42 days.. At the time of inclusion, PfHRP2-based tests were positive in 203 children (99%) and PfLDH-based tests were positive in 204 (99.5%). During follow-up, independent of the treatment received, only 17.3% (28/162) of children effectively cured were negative with the PfHRP2 RDT at day 3, with a gradual increase in specificity until day 42. The specificity of antigen detection with the PfLDH test was 87% (141/162) on day 3, and between 92% and 100% on days 7 to 42. A statistical difference was observed between the persistence of PfHRP2 and PfLDH antigenaemia during follow-up in children treated with artemisinin-based combination therapy (ACT) but not with SP.. Although both RDTs are as sensitive as microscopy in detecting true malaria cases, the PfHRP2 RDT had very low specificity during follow-up until day 28. On the other hand, the PfLDH test could be used to detect failures and, therefore, to assess anti-malarial efficacy.

Topics: Amodiaquine; Antigens, Protozoan; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Benin; Blood; Child, Preschool; Drug Combinations; Drug Monitoring; Drug Therapy, Combination; Ethanolamines; Fluorenes; Follow-Up Studies; Humans; Infant; L-Lactate Dehydrogenase; Malaria, Falciparum; Microscopy; Molecular Diagnostic Techniques; Protozoan Proteins; Pyrimethamine; Sensitivity and Specificity; Sulfadoxine; Treatment Outcome

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Interactions; Drug Resistance, Microbial; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Quinolines; Treatment Outcome

Angola's malaria case-management policy recommends treatment with artemether-lumefantrine (AL). In 2006, AL implementation began in Huambo Province, which involved training health workers (HWs), supervision, delivering AL to health facilities, and improving malaria testing with microscopy and rapid diagnostic tests (RDTs). Implementation was complicated by a policy that was sometimes ambiguous.. Fourteen months after implementation began, a cross-sectional survey was conducted in 33 outpatient facilities in Huambo Province to assess their readiness to manage malaria and the quality of malaria case-management for patients of all ages. Consultations were observed, patients were interviewed and re-examined, and HWs were interviewed.. Ninety-three HWs and 177 consultations were evaluated, although many sampled consultations were missed. All facilities had AL in-stock and at least one HW trained to use AL and RDTs. However, anti-malarial stock-outs in the previous three months were common, clinical supervision was infrequent, and HWs had important knowledge gaps. Except for fever history, clinical assessments were often incomplete. Although testing was recommended for all patients with suspected malaria, only 30.7% of such patients were tested. Correct testing was significantly associated with caseloads < 25 patients/day (odds ratio: 18.4; p < 0.0001) and elevated patient temperature (odds ratio: 2.5 per 1 degrees C increase; p = 0.007). Testing was more common among AL-trained HWs, but the association was borderline significant (p = 0.072). When the malaria test was negative, HWs often diagnosed patients with malaria (57.8%) and prescribed anti-malarials (60.0%). Sixty-six percent of malaria-related diagnoses were correct, 20.1% were minor errors, and 13.9% were major (potentially life-threatening) errors. Only 49.0% of malaria treatments were correct, 5.4% were minor errors, and 45.6% were major errors. HWs almost always dosed AL correctly and gave accurate dosing instructions to patients; however, other aspects of counseling needed improvement.. By late-2007, substantial progress had been made to implement the malaria case-management policy in a setting with weak infrastructure. However, policy ambiguities, under-use of malaria testing, and distrust of negative test results led to many incorrect malaria diagnoses and treatments. In 2009, Angola published a policy that clarified many issues. As problems identified in this survey are not unique to Angola, better strategies for improving HW performance are urgently needed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care Facilities; Angola; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Case Management; Child; Child, Preschool; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Female; Fluorenes; Guideline Adherence; Health Personnel; Health Policy; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Middle Aged; Outpatients; Plasmodium falciparum; Quality of Health Care; Young Adult

Amodiaquine/artesunate and artemether/lumefantrine are currently implemented as antimalarial drugs in Africa. In this study, we assessed Plasmodium falciparum pfmdr1 alleles suggesting reduced sensitivity to amodiaquine/artesunate (86Y-184Y-1246Y) and artemether/lumefantrine (184F and 86N-184F-1246D) in 111 African isolates imported to Germany between 1997 and 2005. pfmdr1 86Y-184Y-1246Y occurred less frequently in West African isolates (2.5%) than in East African parasites (45.8%) (P<0.001) and less frequently in infections contracted in countries currently implementing amodiaquine/artesunate (5.7%) compared with countries with an artemether/lumefantrine policy (20.8%) (P=0.03). pfmdr1 184F showed an opposite pattern. pfmdr1 alleles reveal significant differences between West and East Africa, supporting the current implementation of first-line antimalarials.

Topics: Africa; Alleles; Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Genes, MDR; Genotype; Humans; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Mutation; Plasmodium falciparum

Home Management of Malaria (HMM) is one of the key strategies to reduce the burden of malaria for vulnerable population in endemic countries. It is based on the evidence that well-trained communities health workers can provide prompt and adequate care to patients close to their homes. The strategy has been shown to reduce malaria mortality and severe morbidity and has been adopted by the World Health Organization as a cornerstone of malaria control in Africa. However, the potential fall-out of this community-based strategy on the work burden at the peripheral health facilities level has never been investigated.. A two-arm interventional study was conducted in a rural health district of Burkina Faso. The HMM strategy has been implemented in seven community clinics catchment's area (intervention arm). For the other seven community clinics in the control arm, no HMM intervention was implemented. In each of the study arms, presumptive treatment was provided for episodes of fevers/malaria (defined operationally as malaria). The study drug was artemether-lumefantrine, which was sold at a subsidized price by community health workers/Key opinion leaders at the community level and by the pharmacists at the health facility level. The outcome measured was the proportion of malaria cases among all health facility attendance (all causes diseases) in both arms throughout the high transmission season.. A total of 7,621 children were enrolled in the intervention arm and 7,605 in the control arm. During the study period, the proportions of malaria cases among all health facility attendance (all causes diseases) were 21.0%, (445/2,111, 95% CI [19.3%-22.7%]) and 70.7% (2,595/3,671, 95% CI 68.5%-71.5%), respectively in the intervention and control arms (p << 0.0001). The relative risk ratio for a fever/malaria episode to be treated at the HF level was 30% (0.30 < RR < 0.32). The number of malaria episodes treated in the intervention arm was much higher than in the control arm (6,661 vs. 2,595), with malaria accounting for 87.4% of all disease episodes recorded in the intervention area and for 34.1% in the control area (P < 0.0001). Of all the malaria cases treated in the intervention arm, only 6.7% were treated at the health facility level.. These findings suggest that implementation of HMM, by reducing the workload in health facilities, might contributes to an overall increase of the performance of the peripheral health facilities.

Topics: Adolescent; Adult; Animals; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Communicable Disease Control; Disease Management; Drug Combinations; Ethanolamines; Female; Fluorenes; Health Services Administration; Health Services Research; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Prevalence; Rural Population

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Hearing Loss; Humans; Malaria, Falciparum; Research Design

Topics: Amodiaquine; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Drug Combinations; Drug Resistance, Microbial; Ethanolamines; Fluorenes; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Pyrimethamine; Recurrence; Sulfadoxine

The objective of this study was to investigate complement activation in uncomplicated, early phases of human malaria. Fifteen healthy volunteers were experimentally infected with Plasmodium falciparum malaria. Parasitemia and complement activation products were assessed. During blood stage parasitemia, volunteers showed a significant increase in soluble terminal complement complex (TCC) formation. After start of a curative regimen of artemether/lumefantrine, TCC further increased due to activation of both the classical and the alternative pathway. In-vitro studies confirmed activation of complement by parasite cultures. We thus detected an increase in complement activation in volunteers with experimentally induced malaria, even before parasitemia could be detected microscopically. This significant increase in complement activation occurred despite the possible control of TCC formation by complement regulatory proteins on erythrocytes and the extremely low levels of parasitemia. Treatment with artemether/lumefantrine was followed by classical and alternative pathway complement activation, without evidence for mannan-binding-lectin-mediated complement activation.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biomarkers; Complement Activation; Complement Membrane Attack Complex; Complement System Proteins; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Erythrocyte Membrane; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Middle Aged; Nontherapeutic Human Experimentation; Plasmodium falciparum

Artemether-lumefantrine (AL), presently the most favoured combination therapy against uncomplicated Plasmodium falciparum malaria in Africa, has recently shown to select for the pfmdr1 86N allele. The objective of this study was to search for the selection of other mutations potentially involved in artemether-lumefantrine tolerance and/or resistance, i.e. pfmdr1 gene amplification, pfmdr1 Y184F, S1034C, N1042D, D1246Y, pfcrt S163R and PfATP6 S769N.. The above mentioned SNPs were analysed by PCR-restriction fragment length polymorphism and pfmdr1 gene amplification by real-time PCR based protocols in parasites from 200 children treated with AL for uncomplicated P. falciparum malaria in Zanzibar.. A statistically significant selection of pfmdr1 184F mostly in combination with 86N was seen in reinfections after treatment. No pfmdr1 gene amplification was found.. The results suggest that different pfmdr1 alleles are involved in the development of tolerance/resistance to lumefantrine.

Topics: Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; ATP-Binding Cassette Transporters; Child; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Gene Amplification; Gene Frequency; Genes, MDR; Haplotypes; Humans; Malaria, Falciparum; Mutation; Plasmodium falciparum; Polymorphism, Restriction Fragment Length; Protozoan Proteins; Recurrence; Tanzania

Polymorphisms in the Plasmodium falciparum pfmdr1 gene were assayed in pretreatment samples and in samples from patients reinfected following therapy with artemether-lumefantrine. The pfmdr1 alleles 86N, 184F, and 1246D significantly increased in prevalence after treatment. All samples had a single pfmdr1 copy. Treatment with artemether-lumefantrine selects for polymorphisms that may alter antimalarial drug response.

Topics: Alleles; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Therapy, Combination; Endemic Diseases; Ethanolamines; Fluorenes; Genes, MDR; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymorphism, Genetic; Prevalence; Selection, Genetic; Sesquiterpenes; Uganda

Artemisinin derivatives are becoming the first-line treatment for uncomplicated malaria in areas with widespread resistance to chloroquine. Although generally safe and well tolerated, it has been suggested from animal experiments, and more recently from one human study with artemether-lumefantrine, that these compounds are potentially neurotoxic, affecting particularly the brainstem auditory pathways. We report here the auditory analyses of 15 volunteers who underwent an experimental human malaria infection and were treated with artemether-lumefantrine. The subjects underwent audiological examination before the start of the study, during infection, and after treatment. Examination included standard tone audiometry, high frequency tone audiometry and auditory brainstem response (ABR). No effects on hearing loss that were deemed to be caused by drug treatment were found using tone audiometry. ABR analysis similarly failed to demonstrate any auditory pathway damage in the volunteers after treatment. We have thus not found any clear evidence of a detrimental effect on the auditory system by artemether-lumefantrine treatment in uncomplicated malaria. Our results support the continued implementation of artemisinin derivatives in the fight against drug-resistant malaria.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Audiometry, Pure-Tone; Drug Combinations; Ethanolamines; Evoked Potentials, Auditory, Brain Stem; Female; Fluorenes; Hearing Loss; Humans; Malaria, Falciparum; Male

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Audiometry; Drug Combinations; Ethanolamines; Fluorenes; Hearing Disorders; Humans; Malaria, Falciparum; Sesquiterpenes

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Audiometry; Drug Combinations; Ethanolamines; Fluorenes; Hearing Disorders; Humans; Malaria, Falciparum; Sesquiterpenes

Animal studies have demonstrated artemisinin brain stem toxicity with auditory centres being especially affected; there has, to date, been no evidence of such toxicity with oral artemisinins in humans. Subjects working at a construction site in Mozambique had audiometric assessments taken on joining and leaving the project. Subjects with uncomplicated malarias received co-artemether (artemether-lumefantrine) (n = 150) while age-, gender-, weight- and race-matched controls (n = 150) neither suffered malaria nor received antimalarial therapy. Hearing thresholds were measured at predefined frequencies in treated subjects and controls. Subjects receiving co-artemether had a significantly greater heating loss than controls at all frequencies except 250 Hz and 500 Hz (P values ranging from <0.001 to 0.04, Mann-Whitney U). Mean changes at the different frequencies in subjects ranged from -6.50 dB (95% CI -8.19 to -4.81) [at 1kHz frequency] to -0.07 dB (95% CI -2.19 to 2.05) [at 6 kHz frequency]. Mean changes in the control group ranged from -4.20 dB (95% CI -5.97 to -2.43) [at 1 kHz frequency] to +2.7 dB (95% CI -0.93 to 4.47) [at 6 kHz frequency]. Treatment of uncomplicated malaria with co-artemether is associated with hearing loss, possibly from synergy between potentially ototoxic agents in combination. The safety and neurotoxicity of artemesinins and other endoperoxides needs to be more fully evaluated.

Topics: Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Audiometry; Drug Combinations; Ethanolamines; Female; Fluorenes; Hearing Disorders; Humans; Malaria, Falciparum; Male; Middle Aged; Sesquiterpenes

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Sesquiterpenes

Malaria is a major public health problem representing 2.3% of the overall global disease burden. The cost of treatment of malaria continues to rise as older drugs and insecticides become less effective and are replaced by more effective, but also more expensive products.. A post-hoc pharmacoeconomic analysis (direct and indirect costs only) of three antimalarials, chloroquine, mefloquine and co-artemether, was carried out to address the problem of switch to a more expensive first-line antimalarial in the face of growing chloroquine resistance.. From the perspective of a large public hospital, it was seen that in an area of high grade chloroquine resistance, the total expenditure on patients who fail chloroquine would exceed the excess expenditure on mefloquine when the RII + RIII resistance exceeded 9%.. Switch to a more expensive drug like mefloquine as a first-line option would be cost-effective when the moderate-severe chloroquine resistance exceeded 9%.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Combinations; Economics, Pharmaceutical; Ethanolamines; Female; Fluorenes; Hospitalization; Humans; India; Malaria, Falciparum; Male; Mefloquine; Sesquiterpenes

Topics: Ambulatory Care; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Sesquiterpenes

Topics: Age Factors; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Infant; Malaria, Falciparum; Patient Selection; Practice Guidelines as Topic; Sesquiterpenes; South Africa

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Storage; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Sesquiterpenes; Temperature; Tropical Climate